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Revenue from the Sales of Hematopoietic Stem Cells Transplantation Market to Witness Relatively Significant Growth During 2017 2025 – Canaan Mountain…

By daniellenierenberg

Hematopoietic stem cells are young or immature blood cells found to be living in bone marrow. These blood cells on mature in bone marrow and only a small number of these cells get to enter blood stream. These cells that enter blood stream are called as peripheral blood stems cells. Hematopoietic stem cells transplantation is replacement of absent, diseased or damaged hematopoietic stem cells due to chemotherapy or radiation, with healthy hematopoietic stem cells. Over last 30 years hematopoietic stem cells transplantation market seen rapid expansion and constant expansion with lifesaving technological advances. Hematopoietic stem cells transplantation is also known blood and marrow transplantation which brings about reestablishment of the patients immune and medullary function while treating varied range of about 70 hematological and non-hematological disorders. In general hematopoietic stem cells transplantation is used in treatment of hereditary, oncological, immunological and malignant and non-malignant hematological diseases.

There are two types of peripheral blood stem cell transplants mainly autologous and allogeneic transplantation. In autologous transplants patients own hematopoietic stem cells are harvested or removed before the high-dose treatment that might destroy the patients hematopoietic stem cells. While in allogeneic transplants stem cells are obtained from a tissue type of matched or mismatched donor. Hematopoietic stem cells are harvested from blood or bone marrow and is then frozen to use later. Depending upon the source of hematopoietic stem cells, worldwide there are three types of hematopoietic stem cells transplants namely bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. Major drivers in the hematopoietic stem cells transplantation market are establishment of strong and well developed network of hematopoietic stem cells transplantation organizations having global reach and presence has recognized NGO named Worldwide Network for Blood and Marrow Transplantation Group (WBMT) in official relation with World Health Organization (WHO) and rapid increase in number of transplants. Major restraints in hematopoietic stem cells transplantation market is high cost of transplantation and lack of funding for WBMT and other organizations such as regional, national and donor.

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The global market for Hematopoietic stem cells transplantation market is segmented on basis of transplant type, application, disease indication, end user and geography:

Based on transplantation type, hematopoietic stem cells transplantation market is segmented into allogeneic and autologous. Hematopoietic stem cells transplantation market is also segmented by application type into bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. The market for hematopoietic stem cells transplantation is majorly driven by bone marrow transplant (BMT) segment. Based on end user hematopoietic stem cells transplantation market is segmented into hospitals and specialty centers. Peripheral blood stem cell transplant type holds the largest market for hematopoietic stem cells transplantation. Hematopoietic stem cells transplantation market is further segmented by disease indication into three main categories i.e. lymphoproliferative disorders, leukemia, and non-malignant disorders. Segment lymphoproliferative disorder holds largest share amongst the three in Hematopoietic stem cells transplantation market. On the basis of regional presence, global hematopoietic stem cells transplantation market is segmented into five key regions viz. North America, Latin America, Europe, Asia Pacific, and Middle East & Africa. Europe leads the global hematopoietic stem cells transplantation market followed by U.S. due to easy technological applications, funding and high income populations. Other reasons for rise in hematopoietic stem cells transplantation market is high prevalence of lymphoproliferative disorders and leukemia; demand for better treatment options; and easy accessibility and acceptance of population to new technological advances. Transplantation rates in high income countries are increasing at a greater extent but continued rise is also seen in low income countries and expected to rise more. Hematopoietic stem cells transplantation market will have its potential in near future as being a perfect alternative to traditional system in many congenital and acquired hematopoietic disorders management. While India, China and Japan will be emerging as potential markets. An excellent and long term alternative to relief by side effects of chemotherapy, radiotherapy and immune-sensitive malignancies is another driver for hematopoietic stem cells transplantation market. The key players in global hematopoietic stem cells transplantation market are Lonza, Escape Therapeutics, Cesca Therapeutics Inc., Regen BioPharma, Inc., Invitrx Inc, StemGenex, Lion Biotechnologies, Inc., CellGenix GmbH, Actinium Pharmaceuticals, Inc., Pluristem, Kite Pharma, Novartis AG.

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Approval of Phase I/II Clinical Trial of ATG-016 (Eltanexor), a Second Generation Selective Inhibitor of Nuclear Export (SINE), in Mainland China for…

By daniellenierenberg

SHANGHAI and HONG KONG, Nov. 25, 2020 /PRNewswire/ -- Antengene Corporation Limited ("Antengene", HKSE stock code: 6996.HK), a leading innovative biopharmaceutical company dedicated to discovering, developing and commercializing global first-in-class and/or best-inclass therapeutics in hematology and oncology, announced that the National Medical Products Administration (NMPA) has approved the clinical trial of ATG-016 (eltanexor) in patients with intermediate and higher risk myelodysplastic syndrome (MDS) according to the Revised International Prognostic Scoring System (IPSS-R) after the failure of hypomethylating agents (HMA) based therapy. The trial is a Phase I/II, single-arm, open-label clinical study, aiming to evaluate the pharmacokinetics, safety and efficacy of ATG-016 (eltanexor) monotherapy.

MDS is a heterogeneous group of clonal disorders of the bone marrow hematopoietic stem cells (HPSCs), characterized by ineffective hematopoiesis with peripheral blood cytopenia and a higher risk for developing acute myeloid leukemia (AML). Patients with high-risk MDS refractory to hypomethylating agents have a median overall survival (OS) of only 4 to 6 months with limited options for follow-up treatment. Pre-clinical studies have demonstrated that selective inhibitor of nuclear export (SINE) compounds are able to block the nuclear export of many tumor suppressor proteins (e.g. p53, IkB, p21) leading to their accumulation and activation in the nucleus thereby exerting anti-tumor effects. In addition, SINE compounds can also reduce the nuclear export and translation of many oncogenic mRNA (c-Myc, Bcl-2, Bcl-6, cyclin D) which are bound to elF4E and result in selective apoptosis of tumor cells. ATG-016 is a member of the latest-generation of SINE compounds. Compared to the first-generation nuclear export inhibitor, ATG-016 demonstrates minimal blood-brain barrier permeability and a broader therapeutic window. It has shown preliminary anti-cancer activity in high-risk MDS patients.

Dr. Jay Mei, the Founder, Chairman and CEO of Antengene expressed, "The approval of the ATG-016 clinical trial demonstrates the efficient execution of the Antengene R&D team and is also the first clinical trial approval obtained by Antengene in mainland China after its listing." He also mentioned, "Selinexor, the first-generation selective inhibitor of nuclear export, has shown extensive activity against hematological malignancies and solid tumors, and has been approved by the FDA for relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma. As a second-generation orally available SINE compound, ATG-016 can reduce the blood-brain barrier penetration, thereby representing a broader therapeutic window with potentially less adverse events and better drug tolerability."

About ATG-016

ATG-016 (eltanexor) is a second-generation selective inhibitor of nuclear export compound. Compared to the first-generation SINE compound, ATG-016 has lower blood-brain barrier penetration and broader therapeutic window which allows more frequent dosing and a longer period of exposure at higher levels with better tolerability. Therefore, ATG-016 may be used to target a wider range of indications. We plan to conduct phase I/II clinical studies for MDS in China, and plan to further develop ATG-016 for cancers with high prevalence in the Asia-Pacific region (such as KRAS-mutant solid tumors) and virus infection related malignancies (such as nasopharyngeal carcinoma).

About Antengene

Antengene Corporation Limited ("Antengene", SEHK: 6996.HK) is a leading clinical-stage Asia-Pacific biopharmaceutical company focused on innovative oncology medicines. Antengene aims to provide the most advanced anti-cancer drugs to patients in China, the Asia Pacific Region and around the world. Since its establishment, Antengene has built a pipeline of 12 clinical and pre-clinical stage assets, obtained 10 investigational new drug (IND) approvals and has 9 ongoing cross-regional clinical trials in Asia Pacific. At Antengene, we focus on developing drug candidates with novel mechanisms of action (MoAs) and first-in-class/best-in-class potential to address significant unmet medical needs. The vision of Antengene is to "Treat Patients Beyond Borders" through research, development and commercialization of first-in-class/best-in-class therapeutics.

Forward-looking statements

The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development.

SOURCE Antengene Corporation Limited

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Impact of COVID 19 on Orthopedic Regenerative Medicine Market Detailed Research Study 2020-2027 | Curasan, Inc., Carmell Therapeutics Corporation,…

By daniellenierenberg

Orthopedic Regenerative Medicine Market

Coherent Market Insights, 26-11-2020: The research report on the Orthopedic Regenerative Medicine Market is a deep analysis of the market. This is a latest report, covering the current COVID-19 impact on the market. The pandemic of Coronavirus (COVID-19) has affected every aspect of life globally. This has brought along several changes in market conditions. The rapidly changing market scenario and initial and future assessment of the impact is covered in the report. Experts have studied the historical data and compared it with the changing market situations. The report covers all the necessary information required by new entrants as well as the existing players to gain deeper insight.

Furthermore, the statistical survey in the report focuses on product specifications, costs, production capacities, marketing channels, and market players. Upstream raw materials, downstream demand analysis, and a list of end-user industries have been studied systematically, along with the suppliers in this market. The product flow and distribution channel have also been presented in this research report.

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The segments and sub-section of Orthopedic Regenerative Medicine market are shown below:

By Procedure Cell TherapyTissue EngineeringBy Cell TypeInduced Pluripotent Stem Cells (iPSCs)Adult Stem CellsTissue Specific Progenitor Stem Cells (TSPSCs),Mesenchymal Stem Cells (MSCs)Umbilical Cord Stem Cells (UCSCs)Bone Marrow Stem Cells (BMSCs)By SourceBone MarrowUmbilical Cord BloodAdipose TissueAllograftsAmniotic FluidBy ApplicationsTendons RepairCartilage RepairBone RepairLigament RepairSpine RepairOthers

Some of the key players/Manufacturers involved in the Orthopedic Regenerative Medicine Market are Curasan, Inc., Carmell Therapeutics Corporation, Anika Therapeutics, Inc., Conatus Pharmaceuticals Inc., Histogen Inc., Royal Biologics, Ortho Regenerative Technologies, Inc., Swiss Biomed Orthopaedics AG, Osiris Therapeutics, Inc., and Octane Medical Inc.

If opting for the Global version of Orthopedic Regenerative Medicine Market analysis is provided for major regions as follows:

North America (The US, Canada, and Mexico)

Europe (the UK, Germany, France, and Rest of Europe)

Asia Pacific (China, India, and Rest of Asia Pacific)

Latin America (Brazil and Rest of Latin America)

Middle East & Africa (Saudi Arabia, the UAE, South Africa, and Rest of Middle East & Africa)

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The Orthopedic Regenerative Medicine Market Report Consists of the Following Points:

The report consists of an overall prospect of the market that helps gain significant insights about the global market.

The market has been categorized based on types, applications, and regions. For an in-depth analysis and better understanding of the market, the key segments have been further categorized into sub-segments.

The factors responsible for the growth of the market have been mentioned. This data has been gathered from primary and secondary sources by industry professionals. This provides an in-depth understanding of key segments and their future prospects.

The report analyses the latest developments and the profiles of the leading competitors in the market.

The Orthopedic Regenerative Medicine Market research report offers an eight-year forecast.

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Growing Value of Stem Cells in Medicine to Create a US$2,4 Billion Opportunity for Induced Pluripotent Stem Cell ((iPSC) – GlobeNewswire

By daniellenierenberg

New York, Nov. 25, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Induced Pluripotent Stem Cell (iPSC) Industry" - https://www.reportlinker.com/p05798831/?utm_source=GNW 4 billion by the year 2027, trailing a post COVID-19 CAGR of 6.6%, over the analysis period 2020 through 2027. Stem cells are undifferentiated cells that hold the capability to divide, and differentiate into specialized cells in the body. Stem cells act as repair system and replenish adult tissues, maintaining the turnover of regenerative organs such as the blood and skin. In organs, such as the bone marrow, stem cells frequently form replacement cells to repair the worn out tissue. These cells can respond to signals from the body and transverse a particular developmental pathway to differentiate into one specific cell type. Due to their regenerative properties, stem cells are being researched for therapeutic applications in diabetes, cardiovascular disease, neurodegenerative disease, cancer, autoimmune diseases, spinal cord defects, among others. Stem Cell research is an exciting field where continuous discoveries are being made on new sources of stem cells and new methods of their acquisition and harvesting. Of late, adult stem cells have garnered a lions share of the stem cell space, purely based on the fact that they require less expensive clinical trials, need to comply with fewer regulatory norms and ethical issues compared to other stem cell variants such as embryonic stem cells.

Researchers around the world have been focusing research activities to develop adult stem cell therapies in order to combat a variety of diseases ranging from diabetes to heart disease. Factually, adult stem cells are the only stem cells that have been approved for use in transplants for the treatment of diseases such as cancer. Interestingly, with drug development based on embryonic stem cells being challenged amid growing debate over ethics and regulation of this research, iPSCS offers an alternate step forward in the commercialization of stem cell therapies and regenerative medicine. Embryonic stem cell research continues to remain embroiled in ethical, religious, and political controversies across various countries around the world. Induced Pluripotent Stem Cells (iPSs), which are reprogrammed to mimic embryonic stem cell-like state allowing expression of genes and human cells needed for therapeutic purposes, offers an attractive alternate way forwarding in furthering the goals of stem cell research. Pioneered in 2006 and developed in the following year, these cells are created by conversion of somatic cells into PSCs by introducing certain genes including Myc, Klf4, Oct3/4 and Sox2.

Pluripotent stem cells hold tremendous potential in the regenerative medicine arena. Based on their ability to proliferate indefinitely and develop into desirable cell type such as heart, liver, neuronal and pancreatic cells, iPSCs offer a source of new cells that can replace lost or damaged cells. For instance, iPSCs can be developed into beta islet cells, blood cells or neuronal cells for the treatment of diabetes, leukemia and neurological disorders, respectively. Parkinsons, Alzheimers & spinal cord injuries are key neurologic diseases expected to benefit from iPS research. Dramatic rise in cancer cases worldwide and the need for novel anti-cancer therapies will emerge as a key driver for the growth of iPSCs. Interest in cancer research soars high on new hopes of direct reprogramming of cancer cells with enforced expression of pluripotency factors and the resulting dedifferentiation of transformed cancer cells. The ongoing pandemic is also opening up new opportunities for Human induced pluripotent stem cells (hiPSCs) by offering a reliable model for researchers involved in studying how coronavirus indirectly or directly affects different cells in the human body. Made from a small sample of blood or skin cells, hiPSCs are robust stem cells that can be developed into any cell type and then infected with the coronavirus in order to analyse the disease prognosis and the resulting effects. By deploying hiPSCs, researchers have identified that stem cell-derived cardiomyocytes (heart muscle cells) and blood vessels remain directly exposed to COVID-19 infection. Scientists identified that a significant portion of stem cell-derived cardiomyocytes ceased beating and expired within 3 days after being infected by coronavirus. Researchers can leverage the infected cardiomyocytes to screen for potential drug candidates that can restore their function and improve their survival; and also for identifying new antiviral drugs that potentially curtail coronavirus replication in the heart, reduce cardiac injury and curb the disease prognosis. Researchers can also utilize the infected cardiomyocytes to analyze COVID-induced myocarditis through addition of immune cells to their lab experiments.

Competitors identified in this market include, among others,

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I. INTRODUCTION, METHODOLOGY & REPORT SCOPE I-1

II. EXECUTIVE SUMMARY II-1

1. MARKET OVERVIEW II-1 Impact of Covid-19 and a Looming Global Recession II-1 Induced Pluripotent Stem Cells (iPSCs) Market Gains from Increasing Use in Research for COVID-19 II-1 Studies Employing iPSCs in COVID-19 Research II-2 Stem Cells, Application Areas, and the Different Types: A Prelude II-3 Applications of Stem Cells II-4 Types of Stem Cells II-4 Induced Pluripotent Stem Cell (iPSC): An Introduction II-5 Production of iPSCs II-6 First & Second Generation Mouse iPSCs II-6 Human iPSCs II-7 Key Properties of iPSCs II-7 Transcription Factors Involved in Generation of iPSCs II-7 Noteworthy Research & Application Areas for iPSCs II-8 Induced Pluripotent Stem Cell ((iPSC) Market: Growth Prospects and Outlook II-9 Drug Development Application to Witness Considerable Growth II-11 Technical Breakthroughs, Advances & Clinical Trials to Spur Growth of iPSC Market II-11 North America Dominates Global iPSC Market II-12 Competition II-12 Recent Market Activity II-13 Select Innovation/Advancement II-16

2. FOCUS ON SELECT PLAYERS II-17 Axol Bioscience Ltd. (UK) II-17 Cynata Therapeutics Limited (Australia) II-17 Evotec SE (Germany) II-17 Fate Therapeutics, Inc. (USA) II-17 FUJIFILM Cellular Dynamics, Inc. (USA) II-18 Ncardia (Belgium) II-18 Pluricell Biotech (Brazil) II-18 REPROCELL USA, Inc. (USA) II-18 Sumitomo Dainippon Pharma Co., Ltd. (Japan) II-19 Takara Bio, Inc. (Japan) II-19 Thermo Fisher Scientific, Inc. (USA) II-20 ViaCyte, Inc. (USA) II-20

3. MARKET TRENDS & DRIVERS II-21 Effective Research Programs Hold Key in Roll Out of Advanced iPSC Treatments II-21 Induced Pluripotent Stem Cells: A Giant Leap in the Therapeutic Applications II-21 Research Trends in Induced Pluripotent Stem Cell Space II-22 Exhibit 1: Worldwide Publication of hESC and hiPSC Research Papers for the Period 2008-2010, 2011-2013 and 2014-2016 II-22 Exhibit 2: Number of Original Research Papers on hESC and iPSC Published Worldwide (2014-2016) II-23 Concerns Related to Embryonic Stem Cells Shift the Focus onto iPSCs II-23 Regenerative Medicine: A Promising Application of iPSCs II-24 Induced Pluripotent: A Potential Competitor to hESCs? II-25 Exhibit 3: Global Regenerative Medicine Market Size in US$ Billion for 2019, 2021, 2023 and 2025 II-27 Exhibit 4: Global Stem Cell & Regenerative Medicine Market by Product (in %) for the Year 2019 II-27 Exhibit 5: Global Regenerative Medicines Market by Category: Breakdown (in %) for Biomaterials, Stem Cell Therapies and Tissue Engineering for 2019 II-28 Pluripotent Stem Cells Hold Significance for Cardiovascular Regenerative Medicine II-28 Exhibit 6: Leading Causes of Mortality Worldwide: Number of Deaths in Millions & % Share of Deaths by Cause for 2017 II-30 Leading Causes of Mortality for Low-Income and High-Income Countries II-30 Growing Importance of iPSCs in Personalized Drug Discovery II-31 Persistent Advancements in Genetics Space and Subsequent Growth in Precision Medicine Augur Well for iPSCs Market II-33 Exhibit 7: Global Precision Medicine Market (In US$ Billion) for the Years 2018, 2021 & 2024 II-34 Increasing Prevalence of Chronic Disorders Supports Growth of iPSCs Market II-34 Exhibit 8: Worldwide Cancer Incidence: Number of New Cancer Cases Diagnosed for 2012, 2018 & 2040 II-35 Exhibit 9: Number of New Cancer Cases Reported (in Thousands) by Cancer Type: 2018 II-36 Exhibit 10: Fatalities by Heart Conditions: Estimated Percentage Breakdown for Cardiovascular Disease, Ischemic Heart Disease, Stroke, and Others II-37 Exhibit 11: Rising Diabetes Prevalence Presents Opportunity for iPSCs Market: Number of Adults (20-79) with Diabetes (in Millions) by Region for 2017 and 2045 II-38 Aging Demographics Add to the Global Burden of Chronic Diseases, Presenting Opportunities for iPSCs Market II-38 Exhibit 12: Expanding Elderly Population Worldwide: Breakdown of Number of People Aged 65+ Years in Million by Geographic Region for the Years 2019 and 2030 II-39 Growth in Number of Genomics Projects Propels Market Growth II-39 Genomic Initiatives in Select Countries II-40 Exhibit 13: New Gene-Editing Tools Spur Interest and Investments in Genetics, Driving Lucrative Growth Opportunities for iPSCs: Total VC Funding (In US$ Million) in Genetics for the Years 2014, 2015, 2016, 2017 and 2018 II-41 Launch of Numerous iPSCs-Related Clinical Trials Set to Benefit Market Growth II-41 Exhibit 14: Number of Induced Pluripotent Stem Cells based Studies by Select Condition: As on Oct 31, 2020 II-43 iPSCs-based Clinical Trial for Heart Diseases II-43 Induced Pluripotent Stem Cells for Stroke Treatment II-44 ?Off-the-shelf? Stem Cell Treatment for Cancer Enters Clinical Trial II-44 iPSCs for Hematological Disorders II-44 Market Benefits from Growing Funding for iPSCs-Related R&D Initiatives II-44 Exhibit 15: Stem Cell Research Funding in the US (in US$ Million) for the Years 2016 through 2021 II-46 Human iPSC Banks: A Review of Emerging Opportunities and Drawbacks II-46 Human iPSC Banks Worldwide: An Overview II-48 Cell Sources and Reprogramming Methods Used by Select iPSC Banks II-49 Innovations, Research Studies & Advancements in iPSCs II-50 Key iPSC Research Breakthroughs for Regenerative Medicine II-50 Researchers Develop Novel Oncogene-Free and Virus-Free iPSC Production Method II-51 Scientists Study Concerns of Genetic Mutations in iPSCs II-52 iPSCs Hold Tremendous Potential in Transforming Research Efforts II-52 Researchers Highlight Potential Use of iPSCs for Developing Novel Cancer Vaccines II-54 Scientists Use Machine Learning to Improve Reliability of iPSC Self-Organization II-54 STEMCELL Technologies Unveils mTeSR? Plus II-55 Challenges and Risks Related to Pluripotent Stem Cells II-56 A Glance at Issues Related to Reprogramming of Adult Cells to iPSCs II-57 A Note on Legal, Social and Ethical Considerations with iPSCs II-58

4. GLOBAL MARKET PERSPECTIVE II-59 Table 1: World Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-59

Table 2: World 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets for Years 2020 & 2027 II-60

Table 3: World Current & Future Analysis for Vascular Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-61

Table 4: World 7-Year Perspective for Vascular Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-62

Table 5: World Current & Future Analysis for Cardiac Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-63

Table 6: World 7-Year Perspective for Cardiac Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-64

Table 7: World Current & Future Analysis for Neuronal Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-65

Table 8: World 7-Year Perspective for Neuronal Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-66

Table 9: World Current & Future Analysis for Liver Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-67

Table 10: World 7-Year Perspective for Liver Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-68

Table 11: World Current & Future Analysis for Immune Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-69

Table 12: World 7-Year Perspective for Immune Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-70

Table 13: World Current & Future Analysis for Other Cell Types by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-71

Table 14: World 7-Year Perspective for Other Cell Types by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-72

Table 15: World Current & Future Analysis for Cellular Reprogramming by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-73

Table 16: World 7-Year Perspective for Cellular Reprogramming by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-74

Table 17: World Current & Future Analysis for Cell Culture by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-75

Table 18: World 7-Year Perspective for Cell Culture by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-76

Table 19: World Current & Future Analysis for Cell Differentiation by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-77

Table 20: World 7-Year Perspective for Cell Differentiation by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-78

Table 21: World Current & Future Analysis for Cell Analysis by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-79

Table 22: World 7-Year Perspective for Cell Analysis by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-80

Table 23: World Current & Future Analysis for Cellular Engineering by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-81

Table 24: World 7-Year Perspective for Cellular Engineering by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-82

Table 25: World Current & Future Analysis for Other Research Methods by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-83

Table 26: World 7-Year Perspective for Other Research Methods by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-84

Table 27: World Current & Future Analysis for Drug Development & Toxicology Testing by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-85

Table 28: World 7-Year Perspective for Drug Development & Toxicology Testing by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-86

Table 29: World Current & Future Analysis for Academic Research by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-87

Table 30: World 7-Year Perspective for Academic Research by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-88

Table 31: World Current & Future Analysis for Regenerative Medicine by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-89

Table 32: World 7-Year Perspective for Regenerative Medicine by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-90

Table 33: World Current & Future Analysis for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-91

Table 34: World 7-Year Perspective for Other Applications by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-92

III. MARKET ANALYSIS III-1

GEOGRAPHIC MARKET ANALYSIS III-1

UNITED STATES III-1 Table 35: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-1

Table 36: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-2

Table 37: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-3

Table 38: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-4

Table 39: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-5

Table 40: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-6

CANADA III-7 Table 41: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-7

Table 42: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-8

Table 43: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-9

Table 44: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-10

Table 45: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-11

Table 46: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-12

JAPAN III-13 Table 47: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-13

Table 48: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-14

Table 49: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-15

Table 50: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-16

Table 51: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-17

Table 52: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-18

CHINA III-19 Table 53: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-19

Table 54: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-20

Table 55: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-21

Table 56: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-22

Table 57: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-23

Table 58: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-24

EUROPE III-25 Table 59: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 III-25

Table 60: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK and Rest of Europe Markets for Years 2020 & 2027 III-26

Table 61: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-27

Table 62: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-28

Table 63: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-29

Table 64: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-30

Table 65: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-31

Table 66: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-32

FRANCE III-33 Table 67: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-33

Table 68: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-34

Table 69: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-35

Table 70: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-36

Table 71: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-37

Table 72: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-38

GERMANY III-39 Table 73: Germany Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-39

Table 74: Germany 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-40

Table 75: Germany Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-41

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Growing Value of Stem Cells in Medicine to Create a US$2,4 Billion Opportunity for Induced Pluripotent Stem Cell ((iPSC) - GlobeNewswire

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Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder – Science Advances

By daniellenierenberg

INTRODUCTION

Tissue-resident macrophages regulate immunity and are pivotal for development, homeostasis, and repair (1). Major research efforts have uncovered roles for tissue-resident macrophages during infection, insult, and repair. However, in many cases, these studies disproportionally focus on certain organs in animals while disregarding tissue macrophages in other locations (2). Because function in macrophages is shaped by their tissue of residence and the local environment, specific phenotypes may not be universally applicable to all tissues (3). Notably, the bladder has generally been overlooked in macrophage studies; consequently, the function, origin, and renewal of bladder-resident macrophages in health and disease are poorly characterized or even completely unknown (4, 5).

Tissue-resident macrophages in adult organisms originate from embryonic progenitors, adult bone marrow (BM), or a mixture of both (612). During development, hematopoiesis begins in the yolk sac, giving rise to erythrocytes and macrophages directly and to erythro-myeloid progenitors (EMPs) (6, 13, 14). As hematopoiesis declines in the yolk sac, an intraembryonic wave of definitive hematopoiesis begins in the aorta-gonad-mesonephro, generating hematopoietic stem cells (HSCs). EMPs and then HSCs colonize the fetal liver to give rise to fetal liver monocytes, macrophages, and other immune cells, whereas only HSCs migrate to the BM to establish hematopoiesis in postnatal animals (15). Embryo-derived macrophages can either self-maintain and persist into adulthood or undergo replacement by circulating monocytes at tissue-specific rates. For example, a majority of macrophages in the gut are continuously replenished by BM-derived cells, whereas brain macrophages, or microglia, are long-lived yolk sacderived cells that are not replaced in steady-state conditions (8, 14, 16, 17). In certain conditions, origin influences macrophage behavior; for example, following myocardial infarction, embryonic-derived cardiac macrophages promote tissue repair, whereas BM-derived macrophages induce inflammation (18). However, macrophage functions are also imprinted by their microenvironment (19, 20). In the small intestine, macrophages in the muscle express higher levels of tissue-protective genes, such as Retnla, Mrc1, and Cd163 compared to lamina propria macrophages, although both originate from adult BM (21).

While the origin and maintenance of bladder-resident macrophages are currently unknown, these macrophages do play a role in response to urinary tract infection (UTI), which affects up to 50% of all women at some point in their lifetimes (5, 22). The immune response to uropathogenic Escherichia coli (UPEC) infection in the bladder is characterized by robust cytokine expression leading to rapid infiltration of large numbers of neutrophils and classical Ly6C+ monocytes (2328). Although essential to bacterial clearance, neutrophil and monocyte infiltration likely also induce collateral tissue damage. Targeted depletion of one of these two cell types is associated with reduced bacterial burden after primary infection in mice, whereas elimination of both cell types together leads to unchecked bacteria growth (23, 25, 26). Tissue-resident macrophages also take up a large number of bacteria during UTI; however, depletion of resident macrophages just before infection does not change bacterial clearance in a first or primary UTI (23). The absence of macrophages in the early stages of a primary UTI significantly improves bacterial clearance during a second, or challenge, infection (23). Exactly how the elimination of resident macrophages improves the response to a challenge infection is unclear, particularly as tissue-associated macrophages return to homeostatic numbers in the time interval between the two infections. Of note, improved bacterial clearance is lost in macrophage-depleted mice that are also depleted of CD4+ and CD8+ T cells, suggesting that macrophages modulate T cell activation or limit differentiation of memory T cells, as observed in other tissues (2933). For example, ablation of embryonic-derived alveolar macrophages results in increased numbers of CD8+ resident memory T cells following influenza infection in mice (31). In the gut, monocyte-derived macrophages support the differentiation of CD8+ tissue-resident memory T cells by production of interferon- (IFN-) and interleukin-12 (IL-12) during Yersinia infection (32). The opposing roles of macrophages in modulating T cell responses in the lung and gut support the idea that tissue type and/or ontogeny determines how macrophages may influence adaptive immunity (13).

To understand the role of bladder-resident macrophages, we investigated the origin, localization, and function of these cells during infection. We identified two subpopulations of resident macrophages in nave mouse bladders with distinctive cell surface proteins, spatial distribution, and gene expression profiles. We found that bladder macrophage subsets were long-lived cells, slowly replaced by BM-derived monocytes over the lifetime of the mouse. During UTI, the macrophage subsets differed in their capacity to take up bacteria and survive infection; however, both subsets were replaced by BM-derived cells following resolution of infection. Thus, after a first infection, macrophage subsets had divergent transcriptional profiles compared to their nave counterparts, shaping the response to subsequent UTI.

We reported that macrophage depletion before a first UTI improves bacterial clearance during challenge infection (23). Thus, we initiated a follow-up study to investigate the role of bladder-resident macrophages during UTI. Using the macrophage-associated cell surface proteins CD64 and F4/80 (34, 35), we identified a clear CD64 and F4/80 double-positive resident macrophage population in nave bladders from 7- to 8-week-old female CX3CR1GFP/+ mice. This transgenic mouse is widely used to distinguish macrophage populations in other tissues as the chemokine receptor CX3CR1 is expressed by monocytes and macrophages at some point in their development (36). In most tissues, resident macrophages are either GFP+ as they express CX3CR1 or GFP because they no longer express CX3CR1 (10). Therefore, we were surprised to observe heterogeneity in green fluorescent protein (GFP) expression levels, revealing potentially two subpopulations (Maclo and Machi) of CD64+ F4/80+ macrophages in the bladder (Fig. 1A). Although the differences were small in magnitude, the Machi-expressing population was present in statistically significantly greater numbers and proportions compared to the Maclo population (Fig. 1A). As CX3CR1 deficiency results in decreased macrophage numbers and frequency in the intestine and brain, and the transgenic CX3CR1GFP/+ mouse we used is hemizygous for this receptor (3638), we investigated whether our putative bladder-resident macrophage subsets were similarly present in wild-type C57BL/6 mice. Using the same gating strategy and an anti-CX3CR1 antibody, we clearly identified that CX3CR1 expression levels distinguished two distinct macrophage populations in 7- to 8-week-old nave female wild-type mice (Fig. 1B). Notably, wild-type mice had similar numbers and proportions of each macrophage subset (Fig. 1B).

(A to C) Bladders from 7-week-old female CX3CR1GFP/+ and C57BL6/J mice were analyzed by flow cytometry. (A and B) Dot plots depict the gating strategy for macrophages subsets and graphs show the total cell number (log scale, left) and proportion (right) of bladder macrophage subset, derived from cytometric analysis in (A) CX3CR1GFP/+ and (B) C57BL6/J mice. (C) Histograms show the relative expression of CX3CR1, TIM4, and LYVE1 on macrophage subsets in C57BL6/J mice, Maclo is green and Machi is orange. (See fig. S1 for data on expression of additional proteins). (D) Representative confocal images of bladders from C57BL6/J mice at 20 and 40. Merged images and single channels with the target of interest are shown. DAPI, 4,6-diamidino-2-phenylindole. (E) Graphs show the proportion of each macrophage subset in the lamina propria and muscle of nave C57BL6/J mice. Data are pooled from three experiments, n = 3 to 6 mice per experiment. Each dot represents one mouse; lines are medians. Significance was determined using the nonparametric Mann-Whitney test to compare macrophage subset numbers (A and B) and the nonparametric Wilcoxon matched-pairs signed-rank test to compare the macrophage subset percentages (A, B, and E). All P values are shown; statistically significant P values (<0.05) are in red.

Next, we assessed the surface expression level of proteins known to define macrophage subsets in other tissues (39). We observed that the efferocytic receptor TIM4 and hyaluronan receptor LYVE1 were expressed by the Maclo population, whereas the Machi population was TIM4 and LYVE1 (Fig. 1C). Macrophage-associated proteins, such as CD64, F4/80, CD11b, CD11c, and MHC II, were differentially expressed between the subsets (fig. S1A), supporting the notion that these are distinct populations. A recent publication described several organs as having two distinct macrophage subsets, differentiated by their expression of LYVE1, CX3CR1, and, in particular, MHC II (39). To determine whether bladder macrophage subsets represented these two cell types, we used a similar gating strategy (fig. S1B); however, we observed that MHC II CD64+F4/80+ cells made up a very minor proportion (<2%) of bladder-resident macrophages (fig. SC). Last, to determine whether additional heterogeneity existed within the CD64+ F4/80+ bladder-resident macrophage population, we used the dimension reduction analyses tSNE and UMAP to visualize our data. In our analyses of the nave CD45+ cell population, a large CD64+ cluster contained two putative subsets that corresponded to traditionally gated Maclo and Machi populations and included the tiny proportion of MHC II macrophages (fig. S1D). tSNE (t-distributed stochastic neighbor embedding) and, more particularly, UMAP (uniform manifold approximation and projection) analysis of CD64+ F4/80+ macrophages revealed two groups, with differential expression of CX3CR1, F4/80, CD64, LYVE1, and TIM4, reflecting the data shown in the traditionally gated histograms (fig. S1, D and E). Thus, we concluded that two subsets of macrophages reside in nave mouse bladders with differential surface protein expression.

To determine the spatial orientation of the subsets, we stained nave female C57BL/6 bladders with antibodies to F4/80 and LYVE1 and phalloidin to demarcate the muscle layer from the lamina propria (Fig. 1D). We quantified the number of each subset in these two anatomical locations, observing a higher percentage of the LYVE1+ Maclo macrophage subset in the muscle compared to the LYVE1 Machi macrophage subset (Fig. 1E). Macrophages in the lamina propria were predominantly of the Machi phenotype (Fig. 1E). Thus, the phenotypic differences we observed in bladder-resident macrophage subsets extended to differential tissue localization. Given their spatial organization, we renamed the Maclo subset MacM for muscle and the Machi subset MacL for lamina propria. Together, these results reveal that two phenotypically distinct macrophage subsets reside in different regions of the nave bladder.

We next investigated whether macrophage heterogeneity in adult mouse bladders arose due to distinct developmental origins of the subsets. We analyzed bladders from newborn C57BL/6 pups by confocal imaging and by flow cytometry from CX3CR1-GFPexpressing E16.5 (embryonic day 16.5) embryos and newborn mice. We observed that, in E16.5 and newborn animals, a single CX3CR1hi macrophage population was present in the muscle and lamina propria of the bladder. By flow cytometry, these cells were uniformly positive for CD64 and negative for MHC II as expected for fetal macrophages (40) and stained positively for LYVE1 in confocal images of newborn mouse bladder, supporting that diversification of bladder macrophage subsets occurs after birth (Fig. 2A).

(A) Merged confocal and single channel images from a C57BL/6 newborn mouse bladder. Left image is enlarged at the right. Gating strategy in Cdh5-CreERT2Rosa26tdTomato CX3CR1GFP newborn mice and E16.5 embryos; histograms show CX3CR1 and MHC II expression. (B to E) Reporter recombination in microglia, monocytes, bladder macrophages, and MacM and MacL subsets in Cdh5-CreERT2Rosa26tdTomato mice: (B) E16.5 embryos, newborns 4-hydroxytamoxifen (4OHT)-treated at E7.5, (C) adults 4OHT-treated at E7.5, (D) E16.5 embryos, newborns 4OHT-treated at E10.5, (E) adults 4OHT-treated at E10.5. (F) Percentage of YFP+ cells in microglia, monocytes, MacM, and MacL macrophages in adult Flt3CreRosa26YFP mice. (G to I) Adult shield-irradiated C57BL/6 CD45.2 mice reconstituted with CCR2+/+ CD45.1 BM and C57BL/6 CD45.1 mice reconstituted with CCR2/ CD45.2 BM. Percentage of donor cells (G) in monocytes or (H) bladder-resident macrophages in mice transplanted with CCR2+/+ or CCR2/ BM at 3 and 6 months after transplantation. (See fig. S2 for data on blood leukocyte chimerism). (I) Bladder-resident macrophage replacement rate. Data pooled from two to three experiments, n = 2 to 6 mice per experiment. Each point represents one mouse; lines are medians. Significance determined using the Mann-Whitney test comparing (B to F) macrophages or subsets to monocytes or (G and H) CCR2+/+ to CCR2/ recipients, P values were corrected for multiple testing using the false discovery rate (FDR) method. All P values are shown; statistically significant P values (<0.05) are in red.

We hypothesized that, in adult mice, macrophage subsets arise following differentiation of cells seeded from embryonic progenitors or that one subset is derived from embryonic macrophages, whereas the second subset arises from BM-derived monocytes (41). To test these hypotheses, we used the Cdh5-CreERT2 Rosa26tdTomato transgenic mouse, in which the contribution of distinct hematopoietic progenitor waves to immune cell populations can be followed temporally, such that treatment of pregnant mice with 4-hydroxytamoxifen (4OHT) at E7.5 labels yolk sac progenitors and their progeny and treatment at E10.5 labels HSC that will settle in the BM (adult-type HSCs) and their cellular output (42). After treatment with 4OHT at E7.5, in which microglia were labeled as expected (8, 14), we found a significantly higher proportion of labeled bladder macrophages compared to monocytes in E16.5 embryos and newborn mice (Fig. 2B). Labeled bladder macrophage subsets were nearly absent, similar to monocytes, in adult (8- to 11-week-old) mice (Fig. 2C). These data support the fact that yolk sacderived bladder macrophages are diluted after birth in the adult and suggest that the subsets are composed of HSC-derived macrophages. Low levels of E10.5-labeled macrophages were detected in embryonic bladders (Fig. 2D), and their frequency increased in newborn and adult mice, although to a lesser degree than monocytes, supporting the idea that bladder macrophage subsets arise, at least in part, from adult-type HSCs (Fig. 2, D and E). Of note, both subsets found in the adult bladder showed similar frequencies of E10.5 labeling (Fig. 2E). Together, these results demonstrate that adult bladder macrophages are partially HSC-derived and the macrophage subsets cannot be distinguished from each other by their ontogeny.

To confirm that HSC-derived progenitors contribute to the bladder-resident macrophage pool, we analyzed bladders from adult Flt3Cre Rosa26YFP mice. In this transgenic mouse, expression of the tyrosine kinase receptor Flt3 in multipotent progenitors leads to expression of yellow fluorescent protein (YFP) in the progeny of these cells, such as monocytes, whereas microglia, arising from yolk sac progenitors, are essentially YFP (43). Recombination rates driven by Flt3 are very low during embryonic development, but blood monocyte labeling reaches 80 to 90% in adult mice (7). Therefore, if tissue-resident macrophages arise from postnatal BM-derived monocytes, labeling in adult mice should be similar to blood monocytes, whereas the presence of Flt3 tissue macrophages would indicate that they originated from either embryonic HSCs or adult Flt3-independent progenitors. We observed that, in 2- to 4-month-old and 22- to 24-month-old mice, ~50% of each macrophage subset was YFP+, which was significantly lower compared to circulating monocytes (Fig. 2F). This observation and those from the Cdh5-CreERT2 mice together support the fact that, in addition to adult HSCs, adult bladder macrophage subsets are derived from embryonic progenitors that may include fetal HSCs, and/or later yolk sac progenitors, but with no contribution from early yolk sac progenitors. In addition, the lack of equilibration of YFP labeling in the bladder with blood monocytes at 22 to 24 months suggests that tissue macrophages are not rapidly replaced over the lifetime of the mouse by BM-derived cells in the context of homeostasis.

To determine the replacement rate of bladder-resident macrophages by BM-derived cells in the adult mouse, we evaluated shielded irradiated mice, in which adult animals are irradiated with a lead cover over the bladder to protect this organ from radiation-induced immune cell death and nonhomeostatic immune cell infiltration. Animals were transplanted with congenic BM from wild-type or CCR2/ mice. Monocytes depend on CCR2 receptor signaling to exit the BM into circulation (44). At 3 and 6 months, we observed that a median of 27.7% (3 months) and 27.6% (6 months) of circulating Ly6C+ monocytes were of donor origin in mice reconstituted with wild-type BM, which is well in-line with published studies using this approach (45, 46), whereas only 6.1% (3 months) and 6.5% (6 months) of Ly6C+ monocytes were of donor origin in wild-type mice receiving CCR2/ BM (Fig. 2G). B and natural killer (NK) cells were replenished to a greater extent in mice reconstituted with CCR2/ BM compared to mice reconstituted with CCR2+/+ BM, which could be due to different engraftment efficiencies between CD45.1 and CD45.2 BM (fig. S2) (47, 48). In mice reconstituted with wild-type BM, 4.7% of MacM and 4.5% MacL were of donor origin at 3 months after engraftment. At 6 months after irradiation, 7% of MacM and 8.5% of MacL macrophages were of donor origin (Fig. 2H). Chimerism in bladder macrophage subsets was markedly reduced in CCR2/ BM recipients, suggesting that monocytes slowly replace bladder macrophage subsets in a CCR2-dependent manner (Fig. 2H). By dividing the median macrophage subset chimerism (7 or 8.5%) by the median circulating Ly6C+ monocyte chimerism at 6 months in mice receiving wild-type BM (27.6%), we determined that 25.3% of MacM and 30.8% MacL were replaced by BM-derived monocytes within 6 months (Fig. 2I).

Together, these results reveal that the establishment of distinct bladder-resident macrophage subsets occurs postnatally. Yolk sac macrophages initially seed the fetal bladder but are replaced by fetal HSC-derived macrophages. In adult mice, bladder macrophage subsets are partially maintained through a slow replacement by BM-derived monocytes, although a substantial number of fetally derived cells remain. The incomplete macrophage labeling we observed in our experiments supports the idea that a progenitor source, which cannot be labeled in either model, contributes to resident bladder macrophages. Currently, there is no fate-mapping model to discriminate or follow progeny specifically from late yolk sac EMPs or early fetally restricted HSC, as hematopoietic waves overlap in development. We can conclude that MacM and MacL macrophages do not differ in their developmental origin or rate of replacement by monocytes, supporting the view that one or more unique niches in adult tissue may be responsible for macrophage specialization into phenotypical and functionally distinct macrophage subsets.

Although bladder-resident macrophage subsets had similar ontogeny, their distinct spatial localization and surface protein expression suggested that they have different functions. To test this hypothesis, we first analyzed gene expression profiles of nave adult female MacM and MacL macrophages using bulk RNA sequencing (RNA-seq) (fig. S3A, gating strategy). To formally demonstrate that our cells of interest are macrophages, we aligned the transcriptomes of the bladder macrophage subsets with the macrophage core signature list published by the Immunological Genome Consortium and the bladder macrophage core list from the mouse cell atlas single-cell database (35, 49). The MacM and MacL subsets expressed 80% of the genes from the Immunological Genome Consortium macrophage core signature list and more than 95% of the genes in the bladder macrophage core list (fig. S3B), supporting the idea that our cells of interest are fully differentiated tissue-resident macrophages.

We observed that 1475 genes were differentially expressed between nave MacM and MacL macrophages, in which 899 genes were positively regulated and 576 genes were negatively regulated in the MacL subset relative to MacM macrophages (Fig. 3A). In the top 20 differentially expressed genes (DEG), MacM macrophages expressed higher levels of Tfrc, Ms4a8a, Serpinb6a, CCL24, Scl40a1, Clec10a, and Retnla, all of which are associated with an alternatively activated macrophage phenotype (5053); genes involved in iron metabolism, such as Tfrc, Steap4, and Slc40a1 (54); and genes from the complement cascade, including C4b and Cfp (Fig. 3B). In the same 20 most DEG, MacL macrophages expressed greater levels of Cx3cr1, Cd72, Itgb5, Axl, and Itgav, which are associated with phagocytosis, antigen presentation, and immune response activation (Fig. 3B) (5557). MacL macrophages also expressed inflammatory genes, such as Cxcl16, a chemoattractant for T and NKT cells (58, 59), and Lpcat2 and Pdgfb, which are involved in the metabolism of inflammatory lipid mediators (Fig. 3B) (60, 61). Using gene set enrichment analysis of the DEG to detect pathways up-regulated in the macrophage subsets, we observed that the MacM subset expressed genes linked to pathways such as endocytosis, mineral absorption, lysosome, and phagosome (Fig. 3C). Within the phagosome and endocytosis pathways, genes critical for bacterial sensing and alternative activation such as Tlr4, Mrc1 (encoding for CD206), Cd209, and Egfr (6264) were increased in the MacM subset. In the mineral absorption pathway, genes controlling iron metabolism that also enhance bacterial killing such as Hmox1 and Hmox2 were up-regulated in MacM macrophages (Fig. 3D) (65). In the MacL subset, genes linked to diverse inflammatory pathways, including Toll-like receptor signaling, apoptosis, antigen processing and presentation, and chemokine signaling, were present, as were many infectious and inflammatory diseaserelated pathways (Fig. 3E). Within these pathways, the MacL subset expressed genes related to bacterial sensing, such as Tlr1, Tlr2, and Cd14; initiation of inflammation, such as Il1b, Tnf, Ccl3, Ccl4, Cxcl10, Cxcl16, and Nfkb1; and apoptotic cell death, such as Mapk8, Pmaip1, Bcla1d, Cflar, Bcl2l11, and Birc2 (Fig. 3F).

MacM and MacL macrophages were sorted from 7- to 8-week-old female nave adult C57BL/6 mouse bladders and analyzed by RNA-seq (fig. S3, gating strategy). (A) Heatmaps show the gene expression profile of the 1475 differentially expressed genes and (B) the 20 most differentially expressed genes between the MacM and MacL subsets. (C to F) Using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of significantly up-regulated genes, the following are depicted: (C) pathways enriched in MacM macrophages, (D) up-regulated genes associated with selected pathways in MacM macrophages, (E) pathways enriched in MacL macrophages, and (F) up-regulated genes associated with selected pathways in MacL macrophages. In (C) and (E), the size of the nodes reflects the statistical significance of the term. (Q < 0.05; terms > 3 genes; % genes/term > 3; 0.4).

These findings suggest that MacM macrophages are more anti-inflammatory with increased endocytic activity, which is a common feature of highly phagocytic resident macrophages (66), and as such may play a prominent role in bacterial uptake or killing during infection. MacL, on the other hand, may play a greater role in antigen presentation and initiation or maintenance of inflammation.

As we observed enrichment of genes belonging to endocytosis, lysosome, and phagosome pathways in the MacM subset, we reasoned that the macrophage subsets differentially take up bacteria during infection. To test our hypothesis, we used a well-described mouse model of UTI, in which we transurethrally infect adult female mice via catheterization with 107 colony-forming units (CFU) of UPEC strain UTI89-RFP, which expresses a red fluorescent protein (RFP) (23). At 24 hours post-infection (PI), we investigated bacterial uptake by macrophage subsets (Fig. 4, A and B). Despite that MacM macrophages are farther from the infected urothelium than MacL macrophages, we observed that 20% of MacM and only 10% of MacL subsets contained bacteria at 24 hours PI, providing functional evidence to support the transcriptional data that MacM macrophages have a superior phagocytic capacity compared to MacL macrophages (Fig. 4B). Supporting this conclusion, we found that when we exposed sorted MacM and MacL macrophages to live UPEC in vitro, a greater proportion of MacM macrophages internalized bacteria after 2 hours compared to MacL macrophages (fig. S4A). In addition, despite very low levels of infection overall (~1% of macrophages), more UPEC could be found in MacM macrophages compared to MacL macrophages at 4 hours PI in vivo (fig. S4B). Taking the total population of UPEC-containing macrophages at 24 hours PI, we observed that ~80% of these cells were MacM macrophages, whereas the MacL subset comprised only 20% of this population, which was unusual given that MacM and MacL exist in the bladder in a 1:1 ratio (Fig. 4B and fig. S4C, gating strategy).

(A to H) Female C57BL6/J mice were infected with UTI89-RFP and bladders were analyzed by flow cytometry at (A to D) 24 hours or (E to H) 4 hours PI. (A) Gating strategy, resident macrophage subsets, and cells containing bacteria. (B) Percentage of infected macrophage subsets and UPEC distribution (fig. S4B, gating strategy). (C) IL-4R gMFI (geometric mean fluorescence intensity) in nave mice and 24 hours PI. (D) Total number and frequency of bladder macrophage subsets. (E) Gating strategy. (F) Total number and frequency of bladder macrophage subsets. Percentage of (G) macrophage subsets labeled with a live/dead marker (fig. S4D, gating strategy) and (H) dying macrophages containing UPEC. (I) MacM and MacL macrophage quantification in nave mice and 4 hours PI. (B to D and F to H) Data pooled from three experiments, n = 3 to 6 mice per experiment. (I) Data are pooled from two experiments, n = 2 to 3 mice per experiment. Each dot represents one mouse; lines are medians. In (D) and (F), Mann-Whitney test was used to compare the numbers and the nonparametric Wilcoxon matched-pairs signed-rank test was used to compare the percentages of each macrophage subset. (B and C and G to I) Mann-Whitney test. P values were corrected for multiple testing using the FDR method. All P values are shown; statistically significant P values (<0.05) are in red.

Given the predominance of genes associated with alternatively activated macrophages in the top 20 DEGs of MacM macrophages (Fig. 3B), we measured polarization of the macrophage subsets in nave and infected bladders by analyzing the expression of IL-4R by flow cytometry (Fig. 4C). IL-4R is the receptor of IL-4 and IL-13, two cytokines that drive alternative activation in macrophages (67). Both subsets had increased expression of IL-4R at 24 hours PI compared to their nave counterparts; however, MacM macrophages had consistently higher expression levels of IL-4R compared to MacL macrophages in nave and infected tissue (Fig. 4C).

In the course of our studies, we observed that the total number and proportion of MacL macrophages were significantly lower than those of MacM macrophages at 24 hours PI, whereas, in nave mice, both the number and proportion of the macrophage subsets were equivalent (Figs. 4D and 1B). To rule out the contribution of differentiated monocyte-derived cells to the macrophage pool, we assessed total macrophage cell numbers in the bladder at 4 hours PI, when there is minimal monocyte infiltration (Fig. 4E) (23). Macrophage subset numbers and proportions were significantly different at 4 hours PI (Fig. 4F). As the total numbers of each subset were not increased over nave levels (Fig. 1B), we hypothesized that macrophages die during infection, particularly as apoptosis pathways were more highly expressed in MacL macrophages (Fig. 3, C and D). Using a cell viability dye, which labels dying/dead cells, we found that a significantly higher proportion of MacL macrophages were dying compared to MacM macrophages at 4 hours PI (Fig. 4G and fig. S4D, gating strategy). As UPEC strains can induce macrophage death in vitro (68, 69), we asked whether macrophage cell death was induced by UPEC in vivo. We observed that only 20% of dying or dead cells in each subset were infected (Fig. 4H), suggesting that macrophage death was not primarily driven by UPEC uptake. To determine whether macrophage cell death was confined to a distinct location, we quantified macrophage subset numbers in the muscle and lamina propria. We observed that, at 4 hours PI, only MacL macrophages located in the lamina propria were reduced in numbers compared to nave mice (Fig. 4I). Given that, in the first hours after infection, the urothelium exfoliates massively (70), these results suggest that macrophage death, specifically in the lamina propria, may be due to the loss of a survival factor in this niche. To test whether alteration of the niche induced macrophage death, we chemically induced global urothelial exfoliation by intravesical instillation of protamine sulfate (71, 72). We observed that at 5 hours after treatment, the total numbers of both MacM and MacL subsets were reduced compared to macrophage subsets in nave mice (fig. S4E), suggesting that alterations in bladder urothelium are sufficient to reduce resident macrophage numbers in the bladder, although protamine sulfate may also directly induce macrophage death. Thus, we functionally validated the divergent gene expression observed between macrophage subsets, in which MacM macrophages are more phagocytic and MacL macrophages are more prone to die, supporting the idea that gene expression differences translate to divergent roles for the subsets in response to UTI.

As we observed macrophages dying during infection, we investigated the change in macrophage numbers over time as animals resolved their infection. Both populations significantly decreased at 24 hours PI, then subsequently increased nearly 10-fold at 7 days PI, and returned to numbers just above homeostatic levels at 4 weeks PI (Fig. 5A). With the dynamic increase of macrophage numbers over the course of UTI, we hypothesized that infiltrating monocytes replace resident macrophage subsets during infection, as we previously reported that infiltrating monocytes differentiate to cells resembling macrophages at 48 hours PI (23). To test this hypothesis, we used the CCR2CreERT2 Rosa26tdTomato mouse, in which administration of 4OHT induces recombination in CCR2-expressing cells, such as circulating Ly6C+ monocytes, leading to irreversible labeling of these cells in vivo (73). Blood monocytes and bladder-resident macrophages are not Tomato+ in untreated mice (fig. S5). We administered 4OHT to nave mice and, then, 24 hours later, infected half of the treated mice with 107 CFU of UTI89. At this time point, 24 hours after 4OHT treatment, we analyzed the labeling efficiency in circulating classical Ly6C+ monocytes, finding that approximately 80% of Ly6C+ monocytes were labeled in both nave and infected mice (Fig. 5B). After 6 weeks, when animals had resolved their infection, there were no labeled circulating Ly6C+ monocytes in nave or post-infected mice (Fig. 5B). When we analyzed the bladders of nave mice 6 weeks after the 4OHT pulse, only 2.9% of MacM and 2.1% of MacL macrophage subsets were labeled, supporting our earlier conclusion that monocytes contribute to bladder macrophage subsets at a very slow rate in the steady state (Fig. 5C). At 6 weeks PI, the total numbers of macrophage subsets finally returned to homeostatic levels (Fig. 5D), but PI MacM and MacL macrophages had two to three times more Tomato+ cells (median, MacM 8.4%, MacL 4.4%) than their nave counterparts. These data support the fact that, after monocytes infiltrate the bladder during infection, they remain in the tissue following resolution, integrating themselves into the resident macrophage pool, and thus contribute to the return of macrophage subsets to homeostatic levels.

(A) Total number of MacM (green) and MacL (orange) in nave and 1-, 7-, or 28-day PI mice. (B and C) CCR2CreERT2Rosa26tdTomato mice were pulsed with 4OHT. Twenty-four hours later, half were infected with UTI89-RFP. Percentage of Tomato+ (B) Ly6C+ monocytes 24 hours and 6 weeks after 4OHT-pulse or (C) bladder macrophage subsets 6 weeks after 4OHT-pulse. (D) Total number of macrophage subsets in nave and 6-week PI bladders. (E) Replicate-adjusted principal component analysis of all genes from nave and post-infected bladder macrophage subsets. Differentially expressed genes between nave and 6-week PI (F) MacM (513 genes) and (G) MacL (617 genes) macrophages. KEGG pathway analysis of significantly up-regulated genes, enriched in 6-week PI (H) MacM and (I) MacL macrophages. Up-regulated genes from selected pathways in 6-week PI (J) MacM and (K) MacL macrophages. (A, C, and D) Mann-Whitney test comparing infection to nave. P values were corrected for multiple testing using the FDR method. Higher left-shifted P values refer to MacM and lower right-shifted P values refer to MacL. (H and I) Node size reflects statistical significance of the term (Q < 0.05; terms > 3 genes; %genes/term > 3; 0.4). All P values are shown; statistically significant P values (<0.05) are in red.

As monocytes generally have different origins and developmental programs compared to tissue-resident macrophages, we used RNA-seq to determine whether the macrophage pool in post-infected bladders was different from nave tissue-resident cells. Using principal component analysis (PCA), we compared bladder macrophage subsets from 6-week post-infected mice to their nave counterparts. We found that macrophages clustered more closely together by subset, rather than by infection status, or, in other words, nave and post-infected MacL macrophages clustered more closely to each other than either sample clustered to nave or post-infected MacM macrophages (Fig. 5E). Five hundred thirteen genes (247 genes down-regulated and 266 genes up-regulated) were different between nave and post-infected MacM macrophages (Fig. 5F). Six hundred seventeen genes (401 genes down-regulated and 216 genes up-regulated) were differentially expressed between the nave and post-infected MacL subset (Fig. 5G). Applying gene set enrichment analysis to up-regulated genes in the post-infected macrophage subsets, we detected common pathways between the subsets including enrichment of genes linked to pathways such as antigen presentation; cell adhesion molecules; TH1, TH2, and TH17 cell differentiation; and chemokine signaling pathway (Fig. 5, H and I). Although the enriched genes were not identical within each subset for these pathways, some common up-regulated genes included those encoding for histocompatibility class 2 molecules, such as H2-Ab1, H2-Eb1, H2-DMb1, Ciita, and the Stat1 transcription factor (Fig. 5, I and J). As differentiation of monocytes into macrophages includes up-regulation of cell adhesion and antigen presentation molecules (74), including in the bladder (23), these data further support the idea that monocytes specifically contribute to the PI bladder-resident macrophage pool.

These results show that, in the context of UTI, dying macrophages are replaced by monocyte-derived cells. Tissue-resident macrophage subsets maintain their separate identities distinct from each other after infection, although each subset also takes on a different transcriptional profile compared to their nave counterparts, with up-regulated expression of genes related to adaptive immune responses.

We previously reported that macrophage depletion 24 hours before a primary UTI does not affect bacterial clearance (23). Given that post-infected macrophage subsets up-regulated pathways different from those associated with the transcriptomes of nave bladder macrophage subsets, and that these pathways were linked to inflammatory diseases and the adaptive immune response, we hypothesized that one or both macrophage subsets would mediate improved bacterial clearance to a challenge infection. To test this hypothesis, we infected mice with 107 CFU of kanamycin-resistant UTI89-RFP. Four weeks later, when the infection was resolved, mice were challenged with 107 CFU of the isogenic ampicillin-resistant UPEC strain, UTI89-GFP, and bacterial burden was measured at 24 hours PI. To test the contribution of the macrophage subsets to the response to challenge infection, we used different concentrations of anti-CSF1R depleting antibody to differently target the two macrophage subsets directly before challenge infection (Fig. 6A, experimental scheme). Using 500 g of anti-CSF1R antibody, we depleted 50% of MacM and 80% of MacL macrophages, whereas depletion following treatment with 800 g of anti-CSF1R antibody reduced MacM macrophages by 80% and the MacL subset by more than 90% (Fig. 6B and fig. S6A). Twenty-four hours after anti-CSF1R antibody treatment, the number of circulating neutrophils, eosinophils, NK, B, or T cells was not different from mock-treated mice at either concentration (fig. S6B). Classical Ly6C+ monocytes were modestly reduced in mice treated with 800 g of anti-CSF1R antibody but were unchanged in mice receiving 500 g of depleting antibody. Antibody treatment did not change circulating nonclassical monocyte numbers (fig. S6B). After challenge infection, the bacterial burden was not different in mice treated with 500 g of anti-CSF1R compared to mock-treated mice (Fig. 6C). By contrast, mice depleted with 800 g of anti-CSF1R had reduced bacterial burdens, indicative of a stronger response after challenge compared to nondepleted mice (Fig. 6D).

(A) Experimental scheme. (B) Efficacy of macrophage subset depletion in nave C57BL/6 mice treated with 500 or 800 g of anti-CSF1R antibody. (C and D) Bacterial burden per bladder 24 hours after challenge in female C57BL/6 mice infected with UTI89-RFP according to (A) and treated with phosphate-buffered saline (PBS) (mock) or (C) 500 g or (D) 800 g of anti-CSF1R antibody 72 hours before being challenged with the isogenic UTI89-GFP strain. (E to G) Mice were infected according to (A) and treated with 800 g of anti-CSF1R antibody 72 hours before challenge infection with 107 CFU of the isogenic UTI89-GFP strain. Graphs depict the (E) total number of the indicated cell type, (F) the percentage of the indicated cell type that was infected, and (G) the total number of the indicated cell type that contained UPEC at 24 hours after challenge in mice treated with PBS or 800 g of anti-CSF1R antibody. Data are pooled from three experiments, n = 3 to 6 mice per experiment. Each dot represents one mouse; lines are medians. (C to G) Mann-Whitney test, P values were corrected for multiple testing using the FDR method. All P values are shown; statistically significant P values (<0.05) are in red.

Neutrophils take up a majority of UPEC at early time points during UTI (23). Therefore, we hypothesized that the improved bacterial clearance in macrophage-depleted mice may be due to increased infiltration of inflammatory cells, such as neutrophils. At 24 hours after challenge infection, we observed that, while the numbers of resident macrophage subsets, MHCII+ monocytes, and MHCII monocytes in macrophage-depleted mice were reduced compared to mock-treated mice, as expected, the numbers of infiltrating neutrophils were unchanged by antibody treatment (Fig. 6E and fig. S6C, gating strategy). Fewer eosinophils infiltrated the tissue in macrophage-depleted mice, although the impact of this is unclear as their role in infection is unknown (Fig. 6E). Given that neutrophil infiltration was unchanged and that monocytes, which also take up a large number of bacteria during infection, were reduced in number, we considered that improved bacterial clearance in macrophage-depleted mice may be due to increased bacterial uptake on a per-cell basis during challenge infection. However, bacterial uptake was not different between depleted and mock-treated mice in neutrophils, MHCII+ and MHCII monocytes, or either macrophage subset (Fig. 6F). The lower numbers of the MacM subset in macrophage-depleted mice translated to lower numbers of infected MacM macrophages (Fig. 6, E and G, respectively). However, we observed no differences in the numbers of infected MacL macrophages, neutrophils, and MHCII+ or MHCII monocytes in macrophage-depleted mice compared to nondepleted animals (Fig. 6G). Together, these results support the notion that MacM macrophages negatively affect bacterial clearance in a challenge infection, but not at the level of direct bacterial uptake or myeloid cell infiltration.

As infiltration of inflammatory cells or the number of infected cells during challenge infection was not changed in macrophage-depleted mice, we questioned whether another host mechanism was involved in bacterial clearance. Exfoliation of infected urothelial cells is a host mechanism to eliminate bacteria (70, 75). We hypothesized that macrophage-depleted mice have increased urothelial exfoliation during challenge infection, leading to reduced bacterial numbers. We quantified the mean fluorescence intensity of uroplakins, proteins expressed by terminally differentiated urothelial cells (76), from bladders of post-challenged mice, depleted of macrophages or not (Fig. 7A). We did not detect a significant difference in urothelial exfoliation between mock-treated animals and mice depleted of macrophage before challenge infection, supporting that urothelial exfoliation is not the underlying mechanism behind improved bacterial clearance in macrophage-depleted mice (Fig. 7B). Infiltration of inflammatory cells is associated with bladder tissue damage and increased bacterial burden (26). As we observed fewer monocytes and eosinophils in macrophage-depleted mice during challenge infection, we investigated whether reduced cell infiltration was associated with less tissue damage. We assessed edema formation by quantifying the area of the lamina propria in post-challenged bladders, depleted of macrophages or not (Fig. 7A). We did not detect a difference in edema formation between nondepleted mice and mice depleted of macrophage before challenge infection (Fig. 7C).

Female C57BL/6 mice were infected according to the scheme shown in Fig. 6A and treated with 800 g of anti-CSF1R antibody 72 hours before challenge infection with 107 CFU of UTI89. (A) Representative confocal images of bladders from mice treated with PBS or 800 g of anti-CSF1R antibody 24 hours after challenge. Uroplakin, green; phalloidin, turquoise; DAPI, blue. (B) The graph shows the mean fluorescence intensity of uroplakin expression, quantified from imaging, at 24 hours after challenge. (C) The graph shows the area of the lamina propria, quantified from imaging, at 24 hours after challenge. (D to F) Graphs depict the (D and E) total number of the indicated cell type or (F) the total number of the indicated cell type expressing IFN- at 24 hours after challenge infection. Data are pooled from two experiments, n = 4 to 6 mice per experiment. Each dot represents one mouse; lines are medians. In (B) to (F), significance was determined using the nonparametric Mann-Whitney test and P values were corrected for multiple testing using the FDR method. All calculated/corrected P values are shown and P values meeting the criteria for statistical significance (P < 0.05) are depicted in red.

As we observed fewer eosinophils in macrophage-depleted mice during challenge infection, and our previous work demonstrated that type 2 immune responserelated cytokines are expressed early in UTI (24), we assessed the polarity of the T cell response to challenge infection (fig. S7, gating strategy). Macrophage depletion did not alter the infiltration of T regulatory cells or TH2 or TH17 T helper subsets (Fig. 7D). However, macrophage depletion did correlate with an increase in the numbers of TH1 T cells, NKT cells, NK cells, and type 1 innate lymphoid cells (ILC1s) (Fig. 7E). In macrophage-depleted mice, TH1 T cells, NKT cells, and NK cells had higher IFN- production compared to mock-treated mice (Fig. 7F), suggesting that, in the absence of post-infected macrophages, a more pro-inflammatory, bactericidal response to challenge infection arises in the bladder.

Despite numerous studies of macrophage ontogeny and function in many organs, the developmental origin and role of bladder macrophages are largely unknown. Here, we investigated this poorly understood compartment in homeostasis and a highly inflammatory infectious disease, UTI. A single macrophage population of yolk sac and HSC origin seeds the developing bladder; however, the yolk sac macrophage pool is ultimately replaced at some point after birth. After birth, two subsets, MacM and MacL, arise in the tissue, localizing to the muscle and the lamina propria, respectively. These subsets share similar developmental origin, in that they are primarily HSC-derived and, in adulthood, display a very slow turnover by Ly6C+ monocytes in the steady state. Their distinct transcriptomics support the idea that they play different roles in the bladder, at least in the context of infection. The MacM subset is poised to take up bacteria or potentially infected dying host cells, while polarizing toward a more alternatively activated profile during UTI. MacL macrophages express a profile with greater potential for the induction of inflammation and, whether due to direct consequences of this inflammation or potentially due to loss of the urothelium, undergo pronounced cell death during UTI.

In adult animals, steady-state tissue-resident macrophages are a mix of embryonic and adult monocyte-derived macrophages, with the exception of brain microglia (8, 14). The contributions from embryonic macrophages and circulating adult monocytes to the adult bladder macrophage compartment are similar to that of the lung and kidney (7, 11, 77). Although two macrophage subsets reside in the adult bladder, only a single LYVE1+CX3CR1+ macrophage population was identified in embryonic and newborn bladders. As the bladder is fully formed in newborn mice (78), it is unlikely that macrophage subsets arise to meet the needs of a new structure, as is the case for peritubular macrophages in the testis (41). Rather, although all structures are present, embryonic or prenatal bladder tissue demands are likely distinct from postnatal tissue remodeling in very young mice. For example, in the first weeks after birth, bladder macrophages may support urothelial cells undergoing increased proliferation to establish the three layers of urothelium in adult bladders (79). As these adult tissue niches become fully mature, they may provide different growth or survival factors, driving functional macrophage specialization in discrete locations in the tissue.

In the lung, spleen, BM, and liver, a subpopulation of pro-resolving macrophages are present that phagocytize blood-borne cellular material to maintain tissue homeostasis (66). These macrophages express Mrc1 (encoding for CD206), CD163, and Timd4 (encoding TIM4) (66). MacM macrophages likely represent this subpopulation in the bladder, as they expressed higher levels of genes associated with a pro-resolving phenotype, including the efferocytic receptor TIM4, CD206, and CD163. It is also possible that, similar to muscularis macrophages in the gut, MacM macrophages interact with neurons to control muscle contraction in the bladder and limit neuronal damage during infection (80, 81). By contrast, up-regulated pathways in the MacL subset, in combination with their localization under the urothelium, suggest that, similar to intestinal macrophages, they may regulate T cell responses to bladder microbiota or support urothelial cell integrity (82, 83).

Although it was somewhat unexpected, given that the MacM macrophage subset is located farther from the lumen and urothelium, where infection takes place, we favor the conclusion that MacM macrophages contain more bacteria because they are programmed to do so. This conclusion is supported by the higher expression of genes associated with complement, endocytosis, and phagosome pathways in the MacM subset. It is possible, although challenging to empirically demonstrate, that the MacM subset recognizes dying neutrophils, or even dying MacL macrophages, that have phagocytosed bacteria. We may also consider that, between the subsets, the rate at which bacteria are killed is different, UPEC may survive better in MacM macrophages, MacL macrophages may die after bacterial uptake, the near-luminal location of MacL macrophages may result in their disproportionate sloughing, or even that MacL macrophages break down phagocytosed content better. Additional genetic and knockout models would be needed to address these possibilities.

Significant numbers of MacL macrophages died in the first hours following infection, reflecting their enriched apoptosis pathway. The reduced numbers of both macrophage subsets in protamine sulfate-treated mice suggest that alterations in the urothelium may affect macrophage survival, although we cannot rule out the fact that protamine sulfate directly kills macrophages. Exfoliation induced by protamine sulfate is not comparable to infection, as protamine sulfate induces a rapid, large increase in trans-urothelial conductance (71), suggesting that it induces major disruptions in the urothelium. Protamine sulfate can also suppress cytokine activity and the inflammatory response in the bladder compared to UPEC infection (84). This severe disruption of the urothelium may lead to inadequate supplies of oxygen, nutrients, or survival factors, all of which would be detrimental to macrophage survival. It is less likely that bacteria induce macrophage death as only a small, and importantly equivalent, proportion of both subsets were infected. Instead, MacL macrophage death may be an important step to initiate immune responses to UTI. In the liver, Kupffer cell death by necroptosis during Listeria monocytogenes infection induces recruitment of monocytes, which, in turn, phagocytose bacteria (85). Here, macrophage depletion before challenge infection resulted in decreased infiltration of monocytes, likely due to diminished numbers of these cells in circulation, and fewer eosinophils; however, bacterial burden was also decreased. This suggests that macrophage-mediated immune cell recruitment is not their primary function in the bladder. Infiltration of inflammatory cells is not the only way macrophage cell death regulates infection, however. For instance, pyroptotic macrophages can entrap live bacteria and facilitate their elimination by neutrophils in vivo (86). As MacM macrophages express genes regulating iron metabolism, limiting iron to UPEC would also be a plausible mechanism to control bacterial growth (87).

In the steady state, tissue-resident macrophages can self-maintain locally by proliferation, with minimal input of circulating monocytes (9, 88). By contrast, under inflammatory conditions, resident macrophages are often replaced by monocyte-derived macrophages (85, 8890). Monocytes will differentiate into self-renewing functional macrophages if the endogenous tissue-resident macrophages are depleted or are absent (91, 92). Our results show that UPEC infection induces sufficient inflammation to foster infiltration and differentiation of newly recruited monocytes. It is likely, even, that greater macrophage replacement occurs than we actually measured, as we used a single 4OHT pulse in CCR2CreERT2 Rosa26tdTomato mice 24 hours before infection; however, these cells infiltrate infected bladders over several days. These experiments do not rule out a role for local proliferation in the bladder during UTI, but experiments to test this must be able to distinguish infiltrated monocytes that have already differentiated into tissue macrophages from bona fide tissue-resident macrophages when assessing proliferating cells. These data do support, however, the fact that infiltrating monocytes remain in the tissue, integrated into the resident macrophage pool, after tissue resolution.

Recruited monocyte-derived macrophages can behave differently than resident macrophages when activated, such as in the lung. Gamma herpes virus induces alveolar macrophage replacement by regulatory monocytes expressing higher levels of Sca-1 and MHC II (93). These post-infected mice have reduced perivascular and peribronchial inflammation and inflammatory cytokines, and fewer eosinophils compared to mock-infected mice when exposed to house dust mite to induce allergic asthma (93). Alveolar macrophages of mice infected with influenza virus are replaced by pro-inflammatory monocyte-derived macrophages. At 30 days PI, influenza-infected mice have more alveolar macrophages and increased production of IL-6 when challenged with S. pneumoniae compared to mock-infected mice, leading to fewer deaths (90). Although mechanisms regulating the phenotype of monocyte-derived macrophages are not known, the time of residency in the tissue and the nature of subsequent insults likely influence these cells. The longer that recruited macrophages reside in tissue, the more similar they become to tissue-resident macrophages and no longer provide enhanced protection to subsequent tissue injury (89, 90). In contrast to these studies in the lung, we found that elimination of macrophages, including those recruited during primary infection, led to improved bacterial clearance during secondary challenge, although it is not clear what the long-term consequences on bladder homeostasis might be when a more inflammatory type 1 immune response arises during infection.

Overall, our results demonstrate that two unique subsets of macrophages reside in the bladder. During UTI, these cells respond differently, and a proportion of the population dies. Thus, a first UPEC infection induces replacement of resident macrophage subsets by monocyte-derived cells. When sufficient numbers of MacM macrophages, composed of resident and replaced cells, are depleted, improved bacterial clearance follows, suggesting a major role of this subset in directing the immune response to challenge infection. While these findings greatly improve our understanding of this important immune cell type, much remains to be uncovered, such as the signals and niches that contribute to the establishment of two subsets of bladder-resident macrophages, their roles in the establishment and maintenance of homeostasis, and whether parallel populations and functions exist in human bladder tissue.

This study was conducted using a preclinical mouse model and transgenic mouse strains in controlled laboratory experiments to investigate the origin, maintenance, and function of bladder-resident macrophages in homeostasis and bacterial infection. At the onset of this study, our objective was to understand how bladder-resident macrophages negatively affect the development of adaptive immunity to UTI. Having found two resident macrophage subsets in the course of this work, our objectives were to determine whether these subsets have similar origins and homeostatic maintenance and whether they play divergent roles in response to primary or challenge infection. Mice were assigned to groups upon random partition into cages. In all experiments, a minimum of 2 and a maximum of 10 mice (and more typically 3 to 6 mice per experiment) made up an experimental group and all experiments were repeated two to three times. Sample size was based on our previous work and was not changed in the course of the study. In some cases, n was limited by the number of developing embryos available from timed pregnancies. Data collection is detailed below. Data from all repetitions were pooled before any statistical analysis. As determined a priori, all animals with abnormal kidneys (atrophied, enlarged, and white in color) at the time of sacrifice were excluded from all analyses, as we have observed that abnormal kidneys negatively affect resolution of infection. End points were determined before the start of experiments and researchers were not blinded to experimental groups.

All animals used in this study had free access to standard laboratory chow and water at all times. We used female C57BL/6J mice 7 to 8 weeks old from Charles River, France. Female CX3CR1GFP/+ mice 7 to 8 weeks old were bred in-house. CX3CR1GFP/GFP mice, used to maintain our hemizygous colony, were a gift from F. Chretien (Institut Pasteur). Cdh5-CreERT2 Rosa26tdTomato mice were crossed to CX3CR1GFP mice, producing Cdh5-CreERT2.Rosa26tdTomato.CX3CR1GFP mice at Centre dImmunologie de Marseille-Luminy. In Cdh5-CreERT2.Rosa26tdTomato.CX3CR1GFP mice, cells expressing the CX3CR1 receptor are constitutively GFP+, and treatment with 4OHT conditionally labels hemogenically active endothelial cells (42). We used female and male Cdh5-CreERT2.Rosa26tdTomato.CX3CR1GFP mice 8 to 11 weeks old, at E16.5, and newborns. Flt3Cre.Rosa26YFP mice were a gift from E.G.P. (Institut Pasteur). CCR2/ mice were a gift from M. Lecuit (Institut Pasteur). CCR2creERT2BB mice were a gift from B. Becher (University of Zurich) via S. Amigorena (Institut Curie). CCR2creERT2BB male mice were crossed to Rosa26tdTomato females to obtain CCR2creERT2BB-tdTomato mice at Institut Pasteur. We used female CCR2creERT2BB-tdTomato mice 7 to 8 weeks old. Additional details of the mouse strains used, including JAX and MGI numbers, are listed in table S1. Mice were anesthetized by injection of ketamine (100 mg/kg) and xylazine (5 mg/kg) and euthanized by carbon dioxide inhalation. Experiments were conducted at Institut Pasteur in accordance with approval of protocol number 2016-0010 and dha190501 by the Comit dthique en exprimentation animale Paris Centre et Sud (the ethics committee for animal experimentation), in application of the European Directive 2010/63 EU. Experiments with Cdh5-CreERT2 mice were performed in the laboratory of M. Bajenoff, Centre dImmunologie de Marseille-Luminy, in accordance with national and regional guidelines under protocol number 5-01022012 following review and approval by the local animal ethics committee in Marseille, France.

Antibodies, reagents, and software used in this study are listed in tables S2, S3, and S4, respectively.

Samples were acquired on a BD LSRFortessa using DIVA software (v8.0.1), and data were analyzed by FlowJo (Treestar) software, including the plugins for downsampling, tSNE, and UMAP (version 10.0). The analysis of bladder and blood was performed as described previously (23). Briefly, bladders were dissected and digested in buffer containing Liberase (0.34 U/ml) in phosphate-buffered saline (PBS) at 37C for 1 hour with manual agitation every 15 min. Digestion was stopped by adding PBS supplemented with 2% fetal bovine serum (FBS) and 0.2 M EDTA [fluorescence-activated cell sorting (FACS) buffer]. Fc receptors in single-cell suspensions were blocked with anti-mouse CD16/CD32 and stained with antibodies. Total cell counts were determined by addition of AccuCheck counting beads to a known volume of sample after staining, just before cytometer acquisition. To determine cell populations in the circulation, whole blood was incubated with BD PharmLyse and stained with antibodies (table S2). Total cell counts were determined by the addition of AccuCheck counting beads to 10 l of whole blood in 1-step Fix/Lyse Solution.

For intracellular staining, single-cell suspensions were resuspended in 1 ml of Golgi stop protein transport inhibitor, diluted (1:1500) in RPMI with 10% FBS, 1% sodium pyruvate, 1 Hepes, 1 nonessential amino acid, 1% penicillin-streptomycin, phorbol 12-myristate 13-acetate (50 ng/ml), and ionomycin (1 g/ml), and incubated for 4 hours at 37C. Samples were washed once with FACS buffer, and Fc receptors blocked with anti-mouse CD16/CD32. Samples were stained with antibodies listed in table S2 against surface markers and fixed and permeabilized with 1 fixation and permeabilization buffer and incubated at 4C for 40 to 50 min protected from light. After incubation, samples were washed two times with 1 permeabilization and wash buffer from the transcription factor buffer kit and stained with antibodies against IFN- and the transcriptional factors RORT, GATA3, T-bet, and FoxP3 (table S2), diluted in 1 permeabilization and wash buffer at 4C for 40 to 50 min protected from light. Last, samples were washed two times with 1 permeabilization and wash buffer and resuspended in FACS buffer. Total cell counts were determined by addition of counting beads to a known volume of sample after staining, just before cytometer acquisition.

Whole bladders were fixed with 4% paraformaldehyde (PFA) in PBS for 1 hour and subsequently washed with PBS. Samples were then dehydrated in 30% sucrose in PBS for 24 hours. Samples were cut transversally and embedded in optimal cutting temperature compound, frozen, and sectioned at 30 m. Sections were blocked for 1 hour with blocking buffer [3% bovine serum albumin (BSA) + 0.1% Triton X-100 + donkey serum (1:20) in PBS] and washed three times. Immunostaining was performed using F4/80, LYVE1 antibodies, or polyclonal asymmetrical unit membrane antibodies, recognizing uroplakins [gift from X.-R. Wu, NYU School of Medicine, (76)] (1:200) in staining buffer (0.5% BSA + 0.1% Triton X-100 in PBS) overnight. Sections were washed and stained with phalloidin (1:350) and secondary antibodies (1:2000) in staining buffer for 4 hours. Last, sections were washed and stained with 4,6-diamidino-2-phenylindole. Confocal images were acquired on a Leica SP8 confocal microscope. Final image processing was done using Fiji (version 2.0.0-rc-69/1.52p) and Icy software (v1.8.6.0).

Fate mapping of Cdh5-CreERT2 mice was performed as described previously (42). Briefly, for reporter recombination in offspring, a single dose of 4OHT supplemented with progesterone (1.2 mg of 4OHT and 0.6 mg of progesterone) was delivered by intraperitoneal injection to pregnant females at E7.5 or E10.5. Progesterone was used to counteract adverse effects of 4OHT on pregnancies. To fate map cells in CCR2creERT2BB-tdTomato mice, a single dose (37.5 g/g) of 4OHT injection was delivered intraperitoneally.

For shielded irradiation, 7- to 8-week-old wild-type female CD45.1 or CD45.2 C57BL6/J mice were anesthetized and dressed in a lab-made lead diaper, which selectively exposed their tail, legs, torso, and head to irradiation, but protected the lower abdomen, including the bladder. Mice were irradiated with 9 gray from an Xstrahl x-ray generator (250 kV, 12 mA) and reconstituted with ~3 107 to 4 107 BM cells isolated from congenic (CD45.1) wild-type mice or CD45.2 CCR2/ mice.

Samples were obtained from the whole bladders of nave and 6-week post-infected female C57BL/6J mice. Using FACS, four separate sorts were performed to generate biological replicates, and each sort was a pool of 10 mouse bladders. Macrophage subsets were FACS-purified into 350 l of RLT Plus buffer from the RNeasy Micro Kit plus (1:100) -mercaptoethanol. Total RNA was extracted using the RNeasy Micro Kit following the manufacturers instructions. Directional libraries were prepared using the Smarter Stranded Total RNA-Seq kit Pico Input Mammalian following the manufacturers instructions. The quality of libraries was assessed with the DNA-1000 kit on a 2100 Bioanalyzer, and quantification was performed with Quant-It assays on a Qubit 3.0 fluorometer. Clusters were generated for the resulting libraries with Illumina HiSeq SR Cluster Kit v4 reagents. Sequencing was performed with the Illumina HiSeq 2500 system and HiSeq SBS kit v4 reagents. Runs were carried out over 65 cycles, including seven indexing cycles, to obtain 65-bp single-end reads. Sequencing data were processed with Illumina Pipeline software (Casava version 1.9). Reads were cleaned of adapter sequences and low-quality sequences using cutadapt version 1.11. Only sequences of at least 25 nucleotides in length were considered for further analysis, and the five first bases were trimmed following the library manufacturers instructions. STAR version 2.5.0a (94), with default parameters, was used for alignment on the reference genome (Mus musculus GRCm38_87 from Ensembl version 87). Genes were counted using featureCounts version 1.4.6-p3 (95) from Subreads package (parameters: -t exon -g gene_id -s 1). Count data were analyzed using R version 3.4.3 and the Bioconductor package DESeq2 version 1.18.1 (96). The normalization and dispersion estimation were performed with DESeq2 using the default parameters, and statistical tests for differential expression were performed applying the independent filtering algorithm. A generalized linear model was set to test for the differential expression among the four biological conditions. For each pairwise comparison, raw P values were adjusted for multiple testing according to the Benjamini and Hochberg procedure and genes with an adjusted P value lower than 0.05 were considered differentially expressed. Count data were transformed using variance stabilizing transformation to perform samples clustering and PCA plot. The PCA was performed on the variance-stabilized transformed count matrix that was adjusted for the batch/replicate effect using the limma R package version 3.44.3.

To perform pathway analysis, gene lists of DEGs were imported in the Cytoscape software (version 3.7.2), and analyses were performed using the ClueGO application with the Kyoto Encyclopedia of Genes and Genomes as the database. Significant pathways were selected using the threshold criteria Q < 0.05; terms > 3 genes; % genes/term > 3; 0.4.

We used the human UPEC cystitis isolate UTI89 engineered to express the fluorescent proteins RFP or GFP and antibiotic-resistant cassettes to either kanamycin (UPEC-RFP) or ampicillin (UPEC-GFP) to infect animals for flow cytometric and bacterial burden analyses (23). We used the nonfluorescent parental strain UTI89 for confocal imaging experiments and flow cytometric experiments with CCR2CreERT2 Rosa26tdTomato mice (97). To allow expression of type 1 pili, necessary for infection (98), bacteria cultures were grown statically in Luria-Bertani broth medium for 18 hours at 37C in the presence of antibiotics [kanamycin (50 g/ml) or ampicillin (100 g/ml)]. Primary and challenge UTI were induced in mice as previously described (23, 99). For challenge infection, urine was collected twice a week, for 4 weeks, to follow the presence of bacteria in the urine. Once there were no UTI89-RFP bacteria in the urine, mice were challenged with UTI89-GFP bacteria and euthanized 24 hours after challenge infection. To calculate CFU, bladders were aseptically removed and homogenized in 1 ml of PBS. Serial dilutions were plated on LB agar plates with antibiotics, as required. For in vitro infections, macrophage subsets were sorted from a pool of 10 bladders of nave female C57BL/6J 7- to 8-week-old mice using FACS and 2 103 cells were incubated with 2 104 CFU of UPEC-RFP for 2 hours at 37C. Cells were acquired on a BD LSRFortessa using DIVA software (v8.0.1) and data were analyzed by FlowJo (Treestar) software (version 10.0).

Seven- to 8-week-old wild-type female C57BL6/J mice were anesthetized and instilled intravesically with 50 l of protamine sulfate (50 mg/ml) diluted in PBS and euthanized 5 hours after instillation for analysis.

To produce anti-CSF1R antibody, the hybridoma cell line AFS98 (gift from M. Merad at Icahn School of Medicine at Mount Sinai) (100) was cultured in disposable reactor cell culture flasks for 14 days, and antibodies were purified with disposable PD10 desalting columns. To deplete macrophages, wild-type C57BL/6 mice received intravenous injection of anti-CSF1R antibody (2 mg/ml) diluted in PBS. Animals received two or three intravenous injections, on consecutive days, of anti-CSF1R antibody or PBS. To deplete macrophages with a final concentration of 500 g of anti-CSF1R, we administered 250 g per mouse on day 1 and 250 g per mouse on day 2. To deplete macrophages with a final concentration of 800 g of anti-CSF1R, we administered 400 g per mouse on day 1, 200 g per mouse on day 2, and 200 g per mouse on day 3 to minimize the impact on circulating monocytes.

To quantify macrophage subsets in bladder tissue, six to seven images were randomly acquired of each of the areas of the muscle and lamina propria per mouse in wild-type C57BL/6 female mice with 40 magnification in an SP8 Leica microscope. Maximum intensity Z-projections were performed, and macrophage subsets were counted using Icy software (v1.8.6.0). To quantify urothelial exfoliation and tissue edema, images from whole bladder cross sections were acquired using 20 magnification in an SP8 Leica microscope. Maximum intensity Z-projections were performed, the urothelium was delimited, and mean fluorescence intensity of uroplakin staining was measured using Fiji (v1.51j) software. To quantify tissue edema, the lamina propria was delimited and the area was measured using Fiji software (v1.51j).

Statistical analysis was performed in GraphPad Prism 8 (GraphPad, USA) for Mac OS X applying the nonparametric Wilcoxon test for paired data or the nonparametric Mann-Whitney test for unpaired data in the case of two group comparisons. In the case that more than two groups were being compared or to correct for comparisons made within an entire analysis or experiment, calculated P values were corrected for multiple testing with the false discovery rate (FDR) method (https://jboussier.shinyapps.io/MultipleTesting/) to determine the FDR-adjusted P value. All calculated P values are shown in the figures, and those that met the criteria for statistical significance (P < 0.05) are denoted with red text.

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Everything to Know About Inflamm-aging – NewBeauty Magazine

By daniellenierenberg

Chronic inflammation in the body is linked to cancer, heart disease, diabetes and more, and recently, scientists have discovered that inflammation is also one of the main culprits of skin aging.But what causes it and how do we stop it from getting worse? Weve got the answers below.

Why Inflammation OccursAccording to San Diego, CA dermatologist Zenovia Gabriel, MD, in the body, inflammation stems from an increase in oxygen free radicals that subsequently lead to a cascade of downstream cellular effects. The toxic oxygen radicals trigger inflammatory signals that lead to a host of negative cellular responses, she explains. Skin inflammation is a result of the immune systems response to stimuli or triggers, serving as a defense mechanism to protect your body against injury, infection or cancer.

There are two types of skin inflammation: acute and chronic. Acute inflammation is your bodys immediate response to a physiological insult such as an infection, trauma, stressanything that disrupts your immune system, says Dr. Zenovia. The body expresses inflammation by tissue swelling, warmth, pain or redness, as well as systemic symptoms like fever, aches and fatigue.

Acute inflammatory symptoms generally minimize after several days and eventually normalize, but chronic inflammation implies a longstanding issue that Dr. Zenovia says is often caused by underlying conditions such as autoimmune disorders or chronic infections. Chronic inflammation can be worsened by environmental stressors or unhealthy lifestyle habits, she adds. As we age, our bodies become less efficient at managing the inflammatory response. In addition, chronic low-grade inflammation is common as we age because our bodies and cells are less efficient at regulating this process.

Our diets play a role, too: High blood sugar and poor diet can result in a process called glycation. This leads to protein malfunction in the cells, causing a disruption to normal function, says Dr. Zenovia. In effect, if your body is inflamed and cant handle the level of inflammation, then there are consequences at the cellular and then tissue levelsthis is what we see and feel. We see the cellular disruption manifested on our skin. And these symptoms, such as sagging, wrinkles and brown spots, are all manifestation of cellular disruption and inflammation.

How It Impacts Our SkinThe process is coined inflamm-aging because inflammation ages us, says Dr. Zenovia. Acute inflammation can manifest on the skin as a rashsmooth or scalyredness or warmth in the affected area. Mild low-grade chronic inflammation, such as rosacea or undetectable sun damage often causes skin dryness, dullness, uneven tone, texture, loss of elasticity, or fine lines and wrinkles.Therefore, antioxidants and other actives that specifically target inflammation in the skin are a new frontier for anti-aging. Its not just moisturizers, retinols and hydroxy acidswe need anti-inflammatory support for our skin too.

That undetectable sun damage plays a significant role in the inflammation process. Inflammation is thought to be one of the main causes of skin aging, and the constant exposure to UV radiation from the sun can cause inflammation and DNA damage in the skin, leading to fine lines, wrinkles and spots, says Fort Lauderdale, FL dermatologist Dr. Matthew J. Elias.The single most important product we recommend for skin aging is sunscreen, and while any sunscreen will help protect skin from the untoward effects of chronic UV exposure, the only sunscreen that can actually repair the DNA damage done by the sun is ISDIN Eryfotona Actinica, which actually contains DNA repairsomes that can repair the damage caused by the sun and lessen inflammation.

Dr. Zenovia says an inflammatory cascade can also cause the body to produce more hyaluronidase, the enzyme responsible for breaking down hyaluronic acid (HA), which is critical to skin thickness and health. Fibroblastscollagen-producing cellsare also affected by inflammation, and can become damaged and produce less collagen, she explains. This causes skin to lose its firmness and elasticity.

How to Minimize the EffectsThe first brand to put inflamm-aging skin care on the map, Heraux created a patented molecule called HX-1 that gently exfoliates the skin while helping to prevent inflammation, which is the key ingredient in its Molecular Anti-Inflammaging Serum. HX-1 works directly on skin stem cells to support their peak performance and shield them from stressors that can promote irritation, says Ben Van Handel, PhD, cofounder of Heraux and stem cell biologist at the University of Southern California. Clinical studies of HX-1 have shown significant improvements occurringin the first four weeks without any skin irritation. Daily use of the serum will enable youthful function of skin stem cells longer, increasing the health span of the skin.

Dr. Amir Nobakht, cofounder of Heraux, says its an alternative to retinol without the potential side effects. Retinols historically have had good results but also cause irritation, redness and sun sensitivity, making them unusable for many people. HX-1 on the other hand can accomplish the same goals of a retinol without the harsh side effects. Even those with sensitive skin or who are prone to sunburns can get results without worrying.

One of Dr. Zenovias bestsellers in her Essentials line, Inflam-Aging Night Repair Treatment specifically targets inflammation and is clinically formulated to combat key signs of aging. Everyone could benefit from this product: acne, aging, young and old, she says. This powerhouse night repair treatment features a highly potent triple antioxidant blend of green tea polyphenols, medical-grade resveratrol and caffeine to help reduce inflammation while reducing the appearance of fine lines and wrinkles, and enhancing the look of firm, plump, even-toned skin. Sleep is also really important. Its one of the most restorative things we can do for our bodies and our skin. It decreases stress, lowers inflammation and regenerates our cells.

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‘This is why I’m here’: A Detroit Lions VP tries to save her daughter from rare disease – ESPN

By daniellenierenberg

Detroit Lions senior VP of business development Kelly Kozole works with her daughter, Morgan, who has a rare neurological disorder called beta-propeller protein-associated neurodegeneration, or BPAN.Michael Rothstein

TROY, Mich. -- Wearing a white T-shirt with a massive star in sparkling shades of pink, yellow and seafoam green on the front, Morgan Kozole sits in front of a fold-up chalkboard in the living room of her family's Detroit-area home and starts to draw.

Using pink and yellow chalk, she sketches Mickey and Minnie Mouse. The Disney characters are dominant fixtures in the 5-year-old's life and therefore become a soundtrack for the Kozole family: Morgan constantly saying "Mickey," with her long, blond ponytail bouncing to whatever song happens to be playing on the Mickey Mouse Club.

"These are the two Mickeys," Morgan says, pointing to the chalkboard. Her mother, Detroit Lions senior vice president of business development Kelly Kozole, explains that this is her way of communicating that she would like a visitor to draw Mickey too. If it's close, Morgan accepts it. Another Mickey to fawn over.

For Morgan's birthday earlier this year, the family went to Disney World. On this trip, the Kozoles saw what they had longed for: the potential of progress.

"She knew where we were. She knew Mickey Mouse," Kelly said. "Before, she wouldn't go to the characters, and now she's jumping up and down, hugging. She really, along those lines, is also really into birthdays.

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"The 'Happy Birthday' song. Before that, she was just kind of looking. Sometimes it was too much for her with everyone singing -- sometimes loud noises are too much. This year, we had to sing 'Happy Birthday' to her three times."

Birthdays, for children, are happy occasions -- reasons for grand celebrations of progress toward adulthood. For the rest of Morgan's family it is more complicated.

Morgan has a rare neurological disease called beta-propeller protein-associated neurodegeneration, known as BPAN. It's a disorder, more prevalent in girls than boys, that causes delayed development and seizures, communication issues and, sometimes, motor dysfunction. It's unclear exactly how many people are living with BPAN worldwide due to its rarity, although Dr. Sami Barmada, a scientist at the University of Michigan studying BPAN, estimates roughly 500 to 600 people.

It's rare enough that Dr. Henry Paulson, the director of the Michigan Alzheimer's Disease Center, said there are experts in neurodegeneration who are unfamiliar with BPAN. While Kelly is trying to advocate for her daughter and others with BPAN through fundraising for research, science moves only so fast.

The Kozoles understand that. So birthdays for the family aren't always happy. They are a reminder of what could come.

"That ticking time clock," Kelly said. "Every birthday isn't exciting for me for her. Because it's one year closer to when this bomb is going to go off."

BPAN's rarity makes the reality heartbreakingly simple: There are very few effective treatments, little research and no cure. As Morgan learns how to organize her Peppa Pig characters and learns new words on her iPad -- her future looms.

At some unpredictable point in Morgan's teen and adult years -- the average is around age 25, according to Barmada -- development will just stop. Progress will decline and, in some cases, disappear. Those afflicted with BPAN begin suffering from progressive dystonia parkinsonism -- making it difficult to walk, talk or stand.

"Any day," Kelly said, "it could be like, 'Oh, your daughter's gone.'"

WHEN MORGAN WAS born on Jan. 12, 2015, she was, largely, a healthy baby. She was a little jaundiced but nothing worrisome.

When she would go to the doctor's office for shots, Morgan didn't cry. It was a little abnormal, but when you're a parent of a young child, no crying is viewed as a minor miracle. Kelly and her husband, Kevin, took this as a sign of a tough kid. Nurses even said how great it was.

Looking back, it was a warning sign that something was wrong. BPAN causes a high pain tolerance. Before long, more concerns popped up. Morgan wasn't crawling at nine months, wasn't walking at a year. Expected milestones passed without Morgan reaching them. Kevin and Kelly put her in therapy in late 2016 to work up to these childhood progressive traits and began researching potential causes. They wouldn't find an answer for more than two years.

"She was diagnosed with cerebral palsy at first. One doctor diagnosed her with that, and then another, our neurologist, said she doesn't have that," Kelly said. "Then there was speculation but not a full diagnosis she had autism, so we did all the tests for that.

"So through this kind of journey of trying to find out what was wrong, it was exciting that she didn't have something that you were going to this test for, but you still had so many more questions as you were eliminating all these potential diseases that she could have."

Befuddled, they began genetic testing and in November 2018 received a letter about a mutation on Morgan's WDR45 gene. Kelly Googled it, stumbled upon BPAN and freaked out, calling their neurologist. The neurologist told Kelly not to worry -- BPAN was very rare, and Morgan didn't have it.

Doctors diagnosed her with epilepsy because of seizures. Morgan took Keppra, which helped accelerate her vocabulary to about 50 words, typical for a 1-year-old, when she was 3. Then doctors said no, it wasn't epilepsy either.

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Another meeting with another neurologist led to a different diagnosis. Three days after she and Kevin returned to Michigan from Super Bowl LIII in February 2019, they received a call. Doctors figured out what was wrong.

It was BPAN.

"In my mind, it's worse than cancer," Kelly said. "How is this even possible? That this can even be so painful for kids later on in life. You try so hard to gain all these abilities, and then early adolescence or early adulthood, it's just [gone] one day, and I've seen a lot of these stories.

"There's a BPAN Facebook website, and that's where the doctors sent us. There's no cure. There's no therapy. 'Go to this website.' That's what I was told."

FOR MONTHS KELLY cried, angry and heartbroken. The Kozoles initially told their families and no one else.

In May 2019, Kelly went to her first Neurodegeneration with Brain Iron Accumulation (NBIA) conference. She met other parents, heard their stories and began the new normal.

She used her skills -- organization, fundraising and business -- to brainstorm ways to help. Hardly anyone had researched BPAN. Without it, there would be no chance for a cure -- not in Morgan's lifetime, which could reach her 40s, and not in the lifetime of those who might come after.

She shared what was happening with her boss, Detroit Lions president Rod Wood, and his wife, Susan, using a website link to explain BPAN. Wood knew something was wrong because of texts and emails saying they had to take Morgan to this specialist or that appointment.

"As that was confirmed and became her reality, she is now able to talk about it, in a way," Wood said. "Because she's full bore on trying to help generate awareness and financial resources to find a cure for it.

"She went from the unknown to the very tragic known to, 'OK, what are we going to do about it?'"

Kelly consulted her aunts, both of whom worked in medicine. Linda Narhi worked in biotechnology for Amgen for more than 30 years; Dr. Diane Narhi was the first female chief of staff at Simi Valley (California) Hospital. From talking with another group of fundraising BPAN parents -- BPAN Warriors -- Kelly found a guide.

If her aunts had not been resources, she might have joined BPAN Warriors. But Kelly admittedly needs to be in control, and this was her daughter. She needed to manage this herself. She created a nonprofit called Don't Forget Morgan.

Kelly's aunts provided guidance, and Wood offered contacts he had in the finance industry and Silicon Valley. Wood and Lions general counsel Jay Colvin sit on the board. Other Lions coworkers -- with Wood's blessing -- built the website, designed the logo and created social media plans and the first pitch video for Don't Forget Morgan's rollout in 2020.

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Progress started with a $15,000 grant to help with a mouse model study at Sanford Research in South Dakota, with another, larger, potential grant to come. In recent months, Kelly has focused largely on fundraising, and another parent of a child with BPAN, Christina Mascarenhas Ftikas, has focused on the medical side of the nonprofit.

"This is why I'm here," Kelly said. "I'm supposed to be a vehicle to get all of this awareness and hopefully a cure for BPAN so the child one, two, three, five years from now, there is hope.

"There is no, 'Go to Facebook.' There is something where you can actually give a parent, 'Here's the symptoms to look for.'"

ABOUT AN HOUR away in Ann Arbor, Michigan, Kaci Kegler and her husband, Brian, had been in the same Facebook community. Kelly, new to the group and looking for a nearby connection, wrote Kaci a message.

"Hey, my daughter was just diagnosed, could we connect?"

Kaci understood. She did the same thing, reaching out without success in 2016 after her daughter, Elle, was diagnosed. Kaci wanted to be a resource.

They talked for an hour. There wasn't much Kaci could say to soothe her. Kelly pinged a year later with another message: I'm starting a nonprofit. Kaci offered to help.Despite suffering from BPAN, Morgan is like any other 5-year-old who enjoys playing with her brother, Connor.Michael Rothstein

Days later, on Feb. 28, Kaci and her husband, Brian, an assistant athletic director for development at the University of Michigan, had their yearly fundraiser for BPAN research on Rare Disease Day at Pizza House in Ann Arbor. They met a doctor who had a connection to researchers at Michigan.

"I literally came home and texted [Kelly] and was like, 'Oh my gosh, we may have inroads,'" Kaci said. "We just started texting. I have never met Kelly face-to-face. We still haven't. But we've texted a lot and we've emailed quite a bit.

"It just kind of started."

By summer, they went from nothing to putting pieces in place for a full-fledged research project with a two-year, $140,000 grant for Barmada and Dr. Jason Chua to help start to solve BPAN.

Chua was working on the regulation of autophagy, which is the cleaning out of damaged cells, and studying BPAN became a natural extension of the work he had already been putting in. BPAN alters that in neurons. Barmada said Chua's research provided a "rare win-win situation" to potentially help with BPAN and other diseases too.

"There are a set of questions in BPAN that nobody has the answer to," Barmada said. "And Jason and myself, we just seem to be in the right position, the right place to be able to help out."

The goal is to understand what is happening within BPAN itself and how people end up with it, while also trying to find therapies for existing patients. Within a year, they are hoping to grow stem cells from people with BPAN in their lab, allowing for the creation of their own stem cells missing the WDR45 gene. Then they will try to either replace the gene or "stimulate autophagy through genetic or pharmacologic means," Barmada said. The hope is this can prevent neurodegeneration.

So far, they've hired a research assistant to work with Chua, developed tools to manipulate the gene using the genome-editing tool CRISPR and applied for approval from Michigan and the institutional review board to get skin biopsies to obtain stem cells from BPAN patients.

It's a process, but it's also a start.

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After partnering with Michigan and Sanford, Don't Forget Morgan also began working with Dr. Kathrin Meyer, a researcher at the Center for Gene Therapy at Nationwide Children's Hospital at Ohio State.

"Solving this disease is going to require more than Jason and Sami," Paulson said. "It's going to be a first shot across the bow, but it's going to require more than that. I'll say this, being in the field for a long time. Scientists who are coming up the pike say they want to look at Alzheimer's, want to look at epilepsy. They don't say, 'I want to look at a rare disease.'

"The only way to solve a rare disease is to get someone hooked. Sometimes when you hook a really good one, as I think we have with Jason here, you hook them for life and they make a difference."

MORGAN IS BOUNCING around the Kozoles' suburban Detroit home on this late August day. They just returned from northern Michigan, and having two kids, especially one with special needs, makes tidiness unrealistic.

COVID-19 changed things. Morgan hadn't been to many of her therapies for months. Online school barely kept her attention. There was concern she would have regression in her learning. Instead, her speech advanced by being around Kelly, Kevin and her older brother, Connor, all day. She has sung more songs recently to help increase her vocabulary. Sometimes, she'll listen 20 times in a row.

"Even more than that," Connor said. They aren't sure how much she's truly learning versus memorization. But it is something.Morgan Kozole has inspired her mother, Detroit Lions VP Kelly Kozole, to marshal researchers and other advocates to develop a cure for BPAN, and perhaps help future generations of children who live with the disorder.Michael Rothstein

The family gathers inside Morgan's bedroom -- complete with a special Haven Bed with a zipper to keep her safe from wandering around at night, when she could accidentally turn on the stove and hurt herself or others -- sleep disorders are another BPAN issue. She sits on the floor and starts playing with her small, yellow dollhouse and a fake ice-cream maker. Kelly asks for an ice cream. Morgan makes one for herself instead and pretends to eat it.

Later, outside, Morgan kicks a soccer ball and plays a modified game of catch with a squishy football. Football, no surprise, is big. She says "hike" a lot. "She knows that term," Kevin says, laughing.

In these moments, Morgan seems like any other young child. She attends St. Hugo of the Hills Parish School in Bloomfield Hills, Michigan, but has a one-on-one para nanny to help. She interacts with people, often overly affectionate.

Sitting at the kitchen table after playtime outside, she plays with Starfall, a children's learning app, on her iPad. They hope it accelerates her word recognition. Morgan is entranced watching "Farmer in the Dell" and using her hands to eat orange slices and Cheerios. She needs a mirror in front of her to provide her a target for her mouth. She listens to books, another way to try absorbing information.

Morgan can now count to 20 and say three sentences in a row. Kelly and Kevin have tried to give Morgan a normal life in an abnormal situation, but they worry about the future -- what she won't have and won't be able to experience.

But Morgan has changed some of that outlook too.

"Focus on how she is so loving and has so much pure joy. A lot of parents of special needs [kids] say you can learn so much from these kids, and you really can," Kelly said. "She is, every morning, just so happy, and 'Mama!' Hugs and kisses to strangers. She has none of those behaviors you learn as an adult where you're not kind to people or you don't want to talk to someone.

"She is just open arms, will give you a hug and is so loving, and it's like, 'Wow, this is really what life is about.'"

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Israeli Scientists Discover Oxygen Beauty Treatment That Can Make You Look 25 Years Younger – All You Need to – India.com

By daniellenierenberg

Want to go back in time and look younger? Thats possible now. Yes, you read that right. In a path-breaking discovering, Israeli scientists have made reverse ageing possible. They have found a way to make you look up to 25 years younger. Also Read - Weight Lifting, Sleeping Face-Down And More: Here're 5 Lifestyle Habits That May be Ageing Your Skin

Researchers at Tel Aviv University and the Shamir Medical Centre have collaboratively conducted a study for which they enrolled 35 adults over 64. The subjects were given hyperbaric oxygen treatments (HBOT) 5 times a week for 90 minutes. This continued for three months. Later, the study results published in the journal Ageing showed that the use of this oxygen treatment shortened the ends of the chromosome (telomers) and reversed the accumulation of old body cells. Also Read - 3 Anti-Ageing Essential Oils That Can Offer You Youthful Skin

Notably, ageing depends upon sequences of DNA called telomeres. They are located at the ends of chromosomes and their function is to protect the genetic material contained within. These telomeres shorten and degrade every time a cell divides. This process keeps happening until they become so worn down that they can no longer function. This further results in an unstable or dead chromosome. Also Read - 5 Anti-Ageing Food Items You Must Include in Your Diet to Look Young

One of the study researchers named Professor Shai Efrati said, Today telomere shortening is considered the Holy Grail of the biology of ageing. Researchers around the world are trying to develop pharmacological and environmental interventions that enable telomere elongation. Our HBOT protocol was able to achieve this, proving that the ageing process can, in fact, be reversed at the basic cellular-molecular level.

Hyperbaric Oxygen Treatment (HBOT) is a type of therapy during which a patient is kept in a pressurized chamber where the level of oxygen is increased 3 to 4 times more than what you can breathe at normal air pressure. This aims at treating patients suffering from decompression sickness, brain abscess, severe anemia, who have developed air bubbles in their blood vessels, non-healing wounds, radiation injury, vision loss etc.

When your body gets extra oxygen, it releases growth factors and stem cells that are known to promote healing. In a normal scenario, the oxygen you get through the air is adequate for your body to perform different functions. However, when tissue in your body gets damaged or injured, it needs extra oxygen to survive. Through hyperbaric oxygen treatment, doctors temporarily increase the amount of blood your body is carrying and thus helps maintain the oxygen level in tissue to ensure its survival.

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Stem Cells Market 2020: Rising with Immense Development Trends across the Globe by 2027 – The Market Feed

By daniellenierenberg

Stem Cells Market Overview:

Reports and Data has recently published a new research study titled Global Stem Cells Market that offers accurate insights for the Stem Cells market formulated with extensive research. The report explores the shifting focus observed in the market to offer the readers data and enable them to capitalize on market development. The report explores the essential industry data and generates a comprehensive document covering key geographies, technology developments, product types, applications, business verticals, sales network and distribution channels, and other key segments.

The report is further furnished with the latest market changes and trends owing to the global COVID-19 crisis. The report explores the impact of the crisis on the market and offers a comprehensive overview of the segments and sub-segments affected by the crisis. The study covers the present and future impact of the pandemic on the overall growth of the industry.

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Competitive Landscape:

The global Stem Cells market is consolidated owing to the existence of domestic and international manufacturers and vendors in the market. The prominent players of the key geographies are undertaking several business initiatives to gain a robust footing in the industry. These strategies include mergers and acquisitions, product launches, joint ventures, collaborations, partnerships, agreements, and government deals. These strategies assist them in carrying out product developments and technological advancements.

The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

Celgene Corporation, ReNeuron Group plc, Virgin Health Bank, Biovault Family, Mesoblast Ltd., Caladrius, Opexa Therapeutics, Inc., Precious Cells International Ltd., Pluristem, and Neuralstem, Inc., among others.

An extensive analysis of the market dynamics, including a study of drivers, constraints, opportunities, risks, limitations, and threats have been studied in the report. The report offers region-centric data and analysis of the micro and macro-economic factors affecting the growth of the overall Stem Cells market. The report offers a comprehensive assessment of the growth prospects, market trends, revenue generation, product launches, and other strategic business initiatives to assist the readers in formulating smart investment and business strategies.

To read more about the report, visit @ https://www.reportsanddata.com/report-detail/stem-cells-market

Product Outlook (Revenue, USD Billion; 2017-2027)

Technology Outlook (Revenue, USD Billion; 2017-2027)

Therapy Outlook (Revenue, USD Billion; 2017-2027)

Application Outlook (Revenue, USD Billion; 2017-2027)

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Key Coverage in the Stem Cells Market Report:

Thank you for reading our report. Please get in touch with us if you have any queries regarding the report or its customization. Our team will make sure the report is tailored to meet your requirements.

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Breakthroughs in Stem Cell Based Treatment of Heart Disease – The Connecticut College Voice

By daniellenierenberg

Photo Courtesy of Unsplash.

In the United States alone, one person dies every 36 seconds from cardiovascular disease. Globally, it is also the leading cause of death, claiming over 17 million lives each year. In cases of severe illness, heart transplants have shown great promise in increasing the life expectancy of patients with heart disease. About 75% of heart transplant recipients survive for 5 more years and about 56% survive for 10 more years. However, the average wait times for heart transplants are long, often exceeding 6 months, and some patients simply cannot afford to wait that long.

Therefore, scientists tend to refer to other modes of treatment which rely on managing chronic symptoms, such as hypertension (high blood pressure), diabetes mellitus, obesity, and high cholesterol. This approach, however, does not address the root cause of the problem, which is impaired heart functioning. Since heart cells do not have a mechanism to replace damaged tissue, scientists have become increasingly excited about the possibility of repairing or replacing damaged heart tissue using stem cells (unique cells that have the ability to divide for an extended period of time and differentiate into specialized cells, such as cardiac cells or nerve cells).

Regenerative medicine has been a topic of excitement among researchers for decades. In 1999, Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, was the first to implant lab-grown organs into several patients between 4 and 19 years old. In his method, he obtained bladder cells from the children and coaxed those cells into dividing on a scaffold (a structure that mimics the normal organ). The engineered bladders functioned normally and no ill effects were reported. Pretty much I was able to live a normal life after, said Luke, one of Atalas patients.

More recently, Yoshiki Sawa, a professor of cardiovascular surgery at the University of Osakas medical school, and his team of Japanese researchers successfully transplanted lab-grown cardiac muscles into a human patient. The researchers first extracted adult stem cells from the patients blood or skin and genetically reprogrammed them into induced pluripotent stem (iPS) cells. They were then coaxed into 0.1-millimeter-thick sheets of cardiac tissue and grafted onto the diseased human hearts. According to Sawa, the cells do not seem to integrate into the heart tissue but rather release growth factors (proteins) that help regenerate blood vessels in the damaged muscle tissue and improve cardiac function. The team has conducted an operation on a patient in January 2020, marking the worlds first transplant of cardiac muscle cells.

The United States is also home to major breakthroughs in regenerative medicine. For decades, scientists have utilized embryonic stem cells to engineer heart muscle cells that are able to maintain synchronous breathing in a dish for hours. Despite this major feat, the creation of a working heart called for a more sophisticated technique. Doris Taylor, director of regenerative medicine research at the Texas Heart Institute (THI), has grown in her lab over 100 ghost hearts using protein scaffolds. She creates these scaffolds by first obtaining an animal heart and then decellularizing it by pumping a detergent through its blood vessels to strip away lipids, DNA, soluble proteins, sugars and almost all the other cellular material from the heart, leaving only a pale mesh of collagen, laminins, and the extracellular matrix. This heart does not necessarily have to be a human heart. She often finds pig hearts to be promising tissue because of their considerable safety and unlimited supply. She then recellularizes the heart by injecting it with millions of stem cells and attaching it to artificial lungs and a blood pump. Although her technique has only been used so far for growing animal hearts, she believes that it will eventually be used to create human heart transplants, thus, revolutionizing cardiovascular surgery and putting an end to organ shortage and anti-rejection drugs.

These groundbreaking results in regenerative medicine altogether have taken years of painstaking research to achieve. Taylor believes that her research is exceptionally close to building a working, human-sized heart, and Sawa says that his technique of grafting healthy cardiac muscle sheets onto the patients diseased heart tissue has already helped one of his patients move out of intensive care in just a few days. As the researchers gain more knowledge and get closer to the solution, however, they encounter more challenging obstacles. Sawa, for instance, has found that grafted cells do not always beat in synchrony. Researchers are also split on how these grafts work. On the other hand, investigating the best way to deliver cells still remains a challenge in Taylors research.

Stem cell research in tissue engineering could save millions of lives around the world; therefore, Taylor believes that a coordinated approach among the researchers, clinicians, industry, regulatory bodies and, finally, society should be invigorated to catapult the field forward. For instance, the Twenty-first Century Cures Act can help advance her work by facilitating cooperation among experts and regulatory bodies, providing for accelerated approvals for therapeutic tools in regenerative medicine, and improving the regulation of biologics products. She also maintains that tissue engineering efforts remain poorly funded and believes that more resources must be allocated before her studies can come to life. There is a lot of dependence on societal benevolence, she said. In an interview with RedMedNet, she also said that intense collaboration on a national and an international level is crucial and should be a priority, even though it could be challenging due to scheduling issues and differences in time zones.

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New Insights on the Role of the Mesenchymal-Hematopoietic Stem Cell Axis in Autologous and Allogeneic Hematopoiesis – DocWire News

By daniellenierenberg

This article was originally published here

Stem Cells Dev. 2020 Nov 24. doi: 10.1089/scd.2020.0148. Online ahead of print.

ABSTRACT

Cytoreductive protocols are integral both as conditioning regimens for bone marrow transplantation and as part of therapies for malignancies, but their associated comorbidities represent a long-standing clinical problem. In particular, they cause myeloablation that debilitates the physiological role of mesenchymal stem and precursor cells (MSPCs) in sustaining hematopoiesis. This review addresses the damaging impact of cytoreductive regimens on MSPCs. Additionally, it discusses prospects for alleviating the resulting iatrogenic comorbidities. New insights into the structural and functional dynamics of hematopoietic stem cell (HSC) niches reveal the existence of empty niches and the ability of the donor-derived healthy HSCs to outcompete the defective HSCs in occupying these niches. These findings support the notion that conditioning regimens, conventionally used to ablate the recipient hematopoiesis to create space for engraftment of the donor-derived HSCs, may not be a necessity for allogeneic bone marrow transplantation. Additionally, the capacity of the MSPCs to cross-talk with hematopoietic stem cells, despite MHC disparity, and suppress graft versus host disease indicates the possibility for development of a conditioning-free, MSPCs-enhanced protocol for bone marrow transplantation. The clinical advantage of supplementing cytoreductive protocols with MSPCs to improve autologous hematopoiesis reconstitution and alleviate cytopenia associated with chemo and radiation therapies for cancer is also discussed.

PMID:33231142 | DOI:10.1089/scd.2020.0148

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Global Cell Harvesting Market to Reach US$381,4 Million by the Year 2027 – PRNewswire

By daniellenierenberg

NEW YORK, Nov. 25, 2020 /PRNewswire/ --Amid the COVID-19 crisis, the global market for Cell Harvesting estimated at US$233.2 Million in the year 2020, is projected to reach a revised size of US$381.4 Million by 2027, growing at a CAGR of 7.3% over the period 2020-2027.Manual, one of the segments analyzed in the report, is projected to grow at a 7.9% CAGR to reach US$284.4 Million by the end of the analysis period. After an early analysis of the business implications of the pandemic and its induced economic crisis, growth in the Automated segment is readjusted to a revised 5.6% CAGR for the next 7-year period. This segment currently accounts for a 28.3% share of the global Cell Harvesting market.

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The U.S. Accounts for Over 30.9% of Global Market Size in 2020, While China is Forecast to Grow at a 10.4% CAGR for the Period of 2020-2027

The Cell Harvesting market in the U.S. is estimated at US$72 Million in the year 2020. The country currently accounts for a 30.86% share in the global market. China, the world second largest economy, is forecast to reach an estimated market size of US$34.9 Million in the year 2027 trailing a CAGR of 10.4% through 2027. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 6.1% and 7% respectively over the 2020-2027 period. Within Europe, Germany is forecast to grow at approximately 6.6% CAGR while Rest of European market (as defined in the study) will reach US$34.9 Million by the year 2027.We bring years of research experience to this 5th edition of our report. The 226-page report presents concise insights into how the pandemic has impacted production and the buy side for 2020 and 2021. A short-term phased recovery by key geography is also addressed.

Competitors identified in this market include, among others,

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I. INTRODUCTION, METHODOLOGY & REPORT SCOPE I-1

II. EXECUTIVE SUMMARY II-1

1. MARKET OVERVIEW II-1 Cell Harvesting - A Prelude II-1 Impact of Covid-19 and a Looming Global Recession II-1 With Stem Cells Holding Potential to Emerge as Savior for Healthcare System Struggling with COVID-19 Crisis, Demand for Cell Harvesting to Grow II-1 Select Clinical Trials in Progress for MSCs in the Treatment of COVID-19 II-2 Lack of Antiviral Therapy Brings Spotlight on MSCs as Potential Option to Treat Severe Cases of COVID-19 II-3 Stem Cells Garner Significant Attention amid COVID-19 Crisis II-3 Growing R&D Investments & Rising Incidence of Chronic Diseases to Drive the Global Cell Harvesting Market over the Long-term II-3 US Dominates the Global Market, Asia-Pacific to Experience Lucrative Growth Rate II-4 Biopharmaceutical & Biotechnology Firms to Remain Key End-User II-4 Remarkable Progress in Stem Cell Research Unleashes Unlimited Avenues for Regenerative Medicine and Drug Development II-4 Drug Development II-5 Therapeutic Potential II-5

2. FOCUS ON SELECT PLAYERS II-6 Recent Market Activity II-7 Innovations and Advancements II-7

3. MARKET TRENDS & DRIVERS II-8 Development of Regenerative Medicine Accelerates Demand for Cell Harvesting II-8 The Use of Mesenchymal Stem Cells in Regenerative Medicine to Drive the Cell Harvesting Market II-8 Rise in Volume of Orthopedic Procedures Boosts Prospects for Stem Cell, Driving the Cell Harvesting II-9 Exhibit 1: Global Orthopedic Surgical Procedure Volume (2010- 2020) (in Million) II-11 Increasing Demand for Stem Cell Based Bone Grafts: Promising Growth Ahead for Cell Harvesting II-11 Spectacular Advances in Stem Cell R&D Open New Horizons for Regenerative Medicine II-12 Exhibit 2: Global Regenerative Medicines Market by Category (2019): Percentage Breakdown for Biomaterials, Stem Cell Therapies and Tissue Engineering II-13 Stem Cell Transplants Drive the Demand for Cell Harvesting II-13 Rise in Number of Hematopoietic Stem Cell Transplantation Procedures Propels Market Expansion II-15 Growing Incidence of Chronic Diseases to Boost the Demand for Cell Harvesting II-16 Exhibit 3: Global Cancer Incidence: Number of New Cancer Cases in Million for the Years 2018, 2020, 2025, 2030, 2035 and 2040 II-17 Exhibit 4: Global Number of New Cancer Cases and Cancer-related Deaths by Cancer Site for 2018 II-18 Exhibit 5: Number of New Cancer Cases and Deaths (in Million) by Region for 2018 II-19 Exhibit 6: Fatalities by Heart Conditions: Estimated Percentage Breakdown for Cardiovascular Disease, Ischemic Heart Disease, Stroke, and Others II-19 Exhibit 7: Rising Diabetes Prevalence Presents Opportunity for Cell Harvesting: Number of Adults (20-79) with Diabetes (in Millions) by Region for 2017 and 2045 II-20 Ageing Demographics to Drive Demand for Stem Cell Banking II-20 Global Aging Population Statistics - Opportunity Indicators II-21 Exhibit 8: Expanding Elderly Population Worldwide: Breakdown of Number of People Aged 65+ Years in Million by Geographic Region for the Years 2019 and 2030 II-21 Exhibit 9: Life Expectancy for Select Countries in Number of Years: 2019 II-22 High Cell Density as Major Bottleneck Leads to Innovative Cell Harvesting Methods II-22 Advanced Harvesting Systems to Overcome Centrifugation Issues II-23 Sophisticated Filters for Filtration Challenges II-23 Innovations in Closed Systems Boost Efficiency & Productivity of Cell Harvesting II-23 Enhanced Harvesting and Separation of Micro-Carrier Beads II-24

4. GLOBAL MARKET PERSPECTIVE II-25 Table 1: World Current & Future Analysis for Cell Harvesting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-25

Table 2: World Historic Review for Cell Harvesting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-26

Table 3: World 15-Year Perspective for Cell Harvesting by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets for Years 2012, 2020 & 2027 II-27

Table 4: World Current & Future Analysis for Manual by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-28

Table 5: World Historic Review for Manual by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-29

Table 6: World 15-Year Perspective for Manual by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-30

Table 7: World Current & Future Analysis for Automated by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-31

Table 8: World Historic Review for Automated by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-32

Table 9: World 15-Year Perspective for Automated by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-33

Table 10: World Current & Future Analysis for Peripheral Blood by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-34

Table 11: World Historic Review for Peripheral Blood by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-35

Table 12: World 15-Year Perspective for Peripheral Blood by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-36

Table 13: World Current & Future Analysis for Bone Marrow by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-37

Table 14: World Historic Review for Bone Marrow by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-38

Table 15: World 15-Year Perspective for Bone Marrow by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-39

Table 16: World Current & Future Analysis for Umbilical Cord by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-40

Table 17: World Historic Review for Umbilical Cord by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-41

Table 18: World 15-Year Perspective for Umbilical Cord by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-42

Table 19: World Current & Future Analysis for Adipose Tissue by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-43

Table 20: World Historic Review for Adipose Tissue by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-44

Table 21: World 15-Year Perspective for Adipose Tissue by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-45

Table 22: World Current & Future Analysis for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-46

Table 23: World Historic Review for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-47

Table 24: World 15-Year Perspective for Other Applications by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-48

Table 25: World Current & Future Analysis for Biotech & Biopharma Companies by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-49

Table 26: World Historic Review for Biotech & Biopharma Companies by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-50

Table 27: World 15-Year Perspective for Biotech & Biopharma Companies by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-51

Table 28: World Current & Future Analysis for Research Institutes by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-52

Table 29: World Historic Review for Research Institutes by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-53

Table 30: World 15-Year Perspective for Research Institutes by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-54

Table 31: World Current & Future Analysis for Other End-Uses by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-55

Table 32: World Historic Review for Other End-Uses by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-56

Table 33: World 15-Year Perspective for Other End-Uses by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-57

III. MARKET ANALYSIS III-1

GEOGRAPHIC MARKET ANALYSIS III-1

UNITED STATES III-1 Increasing Research on Stem Cells for Treating COVID-19 to drive the Cell Harvesting Market III-1 Rising Investments in Stem Cell-based Research Favors Cell Harvesting Market III-1 Exhibit 10: Stem Cell Research Funding in the US (in US$ Million) for the Years 2011 through 2017 III-2 A Strong Regenerative Medicine Market Drives Cell Harvesting Demand III-2 Arthritis III-3 Exhibit 11: Percentage of Population Diagnosed with Arthritis by Age Group III-3 Rapidly Ageing Population: A Major Driving Demand for Cell Harvesting Market III-4 Exhibit 12: North American Elderly Population by Age Group (1975-2050) III-4 Increasing Incidence of Chronic Diseases Drives Focus onto Cell Harvesting III-5 Exhibit 13: CVD in the US: Cardiovascular Disease* Prevalence in Adults by Gender & Age Group III-5 Rising Cancer Cases Spur Growth in Cell Harvesting Market III-5 Exhibit 14: Estimated Number of New Cancer Cases and Deaths in the US (2019) III-6 Exhibit 15: Estimated New Cases of Blood Cancers in the US (2020) - Lymphoma, Leukemia, Myeloma III-7 Exhibit 16: Estimated New Cases of Leukemia in the US: 2020 III-7 Market Analytics III-8 Table 34: USA Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-8

Table 35: USA Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-9

Table 36: USA 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-10

Table 37: USA Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-11

Table 38: USA Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-12

Table 39: USA 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-13

Table 40: USA Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-14

Table 41: USA Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-15

Table 42: USA 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-16

CANADA III-17 Market Overview III-17 Exhibit 17: Number of New Cancer Cases in Canada: 2019 III-17 Market Analytics III-18 Table 43: Canada Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-18

Table 44: Canada Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-19

Table 45: Canada 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-20

Table 46: Canada Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-21

Table 47: Canada Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-22

Table 48: Canada 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-23

Table 49: Canada Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-24

Table 50: Canada Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-25

Table 51: Canada 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-26

JAPAN III-27 Increasing Demand for Regenerative Medicine in Geriatric Healthcare and Cancer Care to Drive Demand for Cell Harvesting III-27 Exhibit 18: Japanese Population by Age Group (2015 & 2040): Percentage Share Breakdown of Population for 0-14, 15-64 and 65 & Above Age Groups III-27 Exhibit 19: Cancer Related Incidence and Deaths by Site in Japan: 2018 III-28 Market Analytics III-29 Table 52: Japan Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-29

Table 53: Japan Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-30

Table 54: Japan 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-31

Table 55: Japan Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-32

Table 56: Japan Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-33

Table 57: Japan 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-34

Table 58: Japan Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-35

Table 59: Japan Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-36

Table 60: Japan 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-37

CHINA III-38 Rising Incidence of Cancer Drives Cell Harvesting Market III-38 Exhibit 20: Number of New Cancer Cases Diagnosed (in Thousands) in China: 2018 III-38 Market Analytics III-39 Table 61: China Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-39

Table 62: China Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-40

Table 63: China 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-41

Table 64: China Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-42

Table 65: China Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-43

Table 66: China 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-44

Table 67: China Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-45

Table 68: China Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-46

Table 69: China 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-47

EUROPE III-48 Cancer in Europe: Key Statistics III-48 Exhibit 21: Cancer Incidence in Europe: Number of New Cancer Cases (in Thousands) by Site for 2018 III-48 Ageing Population to Drive Demand for Cell Harvesting Market III-49 Exhibit 22: European Population by Age Group (2016, 2030 & 2050): Percentage Share Breakdown by Age Group for 0-14, 15- 64, and 65 & Above III-49 Market Analytics III-50 Table 70: Europe Current & Future Analysis for Cell Harvesting by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 III-50

Table 71: Europe Historic Review for Cell Harvesting by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-51

Table 72: Europe 15-Year Perspective for Cell Harvesting by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK and Rest of Europe Markets for Years 2012, 2020 & 2027 III-52

Table 73: Europe Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-53

Table 74: Europe Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-54

Table 75: Europe 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-55

Table 76: Europe Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-56

Table 77: Europe Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-57

Table 78: Europe 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-58

Table 79: Europe Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-59

Table 80: Europe Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-60

Table 81: Europe 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-61

FRANCE III-62 Table 82: France Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-62

Table 83: France Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-63

Table 84: France 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-64

Table 85: France Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-65

Table 86: France Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-66

Table 87: France 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-67

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Global Cell Harvesting Market to Reach US$381,4 Million by the Year 2027 - PRNewswire

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Dr Apar Kishor Ganti Outlines the Effectiveness of Lurbinectedin and Benefits Over Competition – AJMC.com Managed Markets Network

By daniellenierenberg

Lurbinectedin is being studied in a number of diseases, but in lung cancer it has a more favorable side effect profile compared with topotecan, said Apar Kishor Ganti, MD, University of Nebraska Medical Center.

Lurbinectedin is being studied in a number of diseases, but in lung cancer it has a more favorable side effect profile compared with topotecan, said Apar Kishor Ganti, MD, professor of internal medicine, Division of Oncology & Hematology, University of Nebraska Medical Center.

Are there other tumor types where lurbinectedin seems to hold promise?

So, lurbinectedin is being studied in other diseases like breast cancer, mesothelioma, chronic lymphocytic leukemia, among others. But the difference in these other conditions compared to small cell [lung cancer] is there are other treatment options that are reasonably effective in these other cancers, unlike in small cell, so that's where it becomes much more important in in this particular setting.

One other reason why lurbinectedin may be effective is, like I told you earlier, there is a group of cells that seem to be shielded from chemotherapy. We call them cancer stem cells. And there are some lab data that suggests that lurbinectedin may inhibit cancer stem cells, as well. Again, this is all preliminary data. And we don't necessarily know if that occurs in humans or not, but those are some of the hypothesized mechanisms of action.

What other advantages are there of lurbinectedin over topotecan?

One of the other advantages of lurbinectedin over topotecan is that topotecan has to be given 5 days in a row, whereas lurbinectedin is given just once every 3 weeks. And the side effect profile of lurbinectedin seems to be favorable. The main side effect of lurbinectedin is bone marrow suppression, anemia, leukopenia, neutropenia, [and] thrombocytopenia, but they seem to occur in about 5% to 10% of patients. And so, that's another possible advantage of lurbinectedin over for some of the other drugs that are available.

As far as small cell lung cancer itself is concerned, even though there is a lot of research going on in small cell, multiple different drugs have been triedtargeted therapies, immunotherapythere is some evidence to suggest that immunotherapy helps with chemotherapy in the frontline setting. But immunotherapy by itself in patients who have failed chemotherapy does not seem to be much more effective. People have tried targeted therapies, again, not one of them has shown to have any meaningful benefit for these patients. So that has been very disappointing.

There have been multiple drugs that have been studied. Unfortunately, none of them have had a significant benefit so far. So, it's a fairly difficult to treat disease. And like I mentioned earlier, even though it seems to respond quite well to initial chemotherapymost patients relapse and very few are cured even if they present with very early stage disease. And that's why it's a very challenging disease to treat.

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Dr Apar Kishor Ganti Outlines the Effectiveness of Lurbinectedin and Benefits Over Competition - AJMC.com Managed Markets Network

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Stem Cell Therapy Market is estimated to be worth USD 8.5 Billion by 2030, claims Roots Analysis – Cheshire Media

By daniellenierenberg

With multiple approved products, the field of stem cell therapies has gained substantial momentum over the last decade; several innovator companies are currently progressing their proprietary therapy candidates with cautious optimism. In fact, recent studies suggest that mesenchymal stem cells have the potential to end the Coronavirus (COVID-19) pandemic.

Roots Analysis is pleased to announce the publication of its recent study, titled, Global Stem Cells Market: Focus on Clinical Therapies, 20202030 (Based on Source (Allogeneic, Autologous); Origin (Adult, Embryonic); Type (Hematopoietic, Mesenchymal, Progenitor); Lineage (Amniotic Fluid, Adipose Tissue, Bone Marrow, Cardiosphere, Chondrocytes, Corneal Tissue, Cord Blood, Dental Pulp, Neural Tissue Placenta, Peripheral Blood, Stromal Cells); and Potency (Multipotent, Pluripotent)).

The report features an extensive study of the current market landscape, offering an informed opinion on the likely adoption of these therapeutics over the next decade. The report features an in-depth analysis, highlighting the capabilities of various stakeholders engaged in this domain. In addition to other elements, the study includes:

A detailed market forecast, featuring analysis of the current and projected future opportunity across key market segments (listed below)

Source of Stem Cell

Origin of Stem Cell

Type of Stem Cell

Lineage of Stem Cell

Route of Administration

Therapeutic Area

End Users

Key Geographical Regions

Transcripts of interviews held with the following senior level representatives of stakeholder companies

Key companies covered in the report

For more information, please click on the following link:

https://www.rootsanalysis.com/reports/view_document/stem-cells-market/296.html/

About Roots Analysis

Roots Analysis is one of the fastest growing market research companies, sharing fresh and independent perspectives in the bio-pharmaceutical industry. The in-depth research, analysis and insights are driven by an experienced leadership team which has gained many years of significant experience in this sector. If youd like help with your growing business needs, get in touch at [emailprotected]

Contact Information

Roots Analysis Private Limited

Gaurav Chaudhary

+1 (415) 800 3415

[emailprotected]

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Stem Cell Therapy Market is estimated to be worth USD 8.5 Billion by 2030, claims Roots Analysis - Cheshire Media

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MSK Study Is the First to Link Microbiota to Dynamics of the Human Immune System – On Cancer – Memorial Sloan Kettering

By daniellenierenberg

Summary

MSK researchers have uncoveredan important finding about the relationship between the microbiota and the immune system, showing for the first time that the concentration of different types of immune cells in the blood changes in relation to the presence of different bacterial strains in the gut.

In recent years, the microbiota the community of bacteria and other microorganisms that live on and in the human body has captured the attention of scientists and the public, in part because its become easier to study. It has been linked to many aspects of human health.

A multidisciplinary team from Memorial Sloan Kettering has shown for the first time that the gut microbiota directly shapes the makeup of the human immune system. Specifically, their research demonstrated that the concentration of different types of immune cells in the blood changed in relation to the presence of different bacterial strains in the gut. The results of their study, which used more than ten years of data collected from more than 2,000 patients, is being published November 25, 2020, in Nature.

The scientific community had already accepted the idea that the gut microbiota was important for the health of the human immune system, but the data they used to make that assumption came from animal studies, says Sloan Kettering Institute systems biologist Joao Xavier, co-senior author of the paper together with his former postdoc Jonas Schluter, who is now an assistant professor at NYU Langone Health. At MSK, we have a remarkable opportunity to follow how the composition of the microbiota changes in people being treated for blood cancers, Dr. Xavier adds.

(From left) Researchers Emily Fontana, Luigi Amoretti, Joao Xavier, Roberta Wright, and Jonas Schluter in the lab.

The data that were used in the study came from people receiving allogeneic stem cell and bone marrow transplants (BMTs). After strong chemotherapy or radiation therapy is used to destroy cancerous blood cells, the patients blood-forming system is replaced with stem cells from a donor. For the first few weeks until the donors blood cells including the white blood cells that make up the immune system have established themselves, the patients are extremely vulnerable to infections. To protect them during this time, patients are given antibiotics.

But many of these antibiotics have the unwanted side effect of destroying healthy microbiota that live in the gut, allowing dangerous strains to take over. When the patients immune system has reconstituted, the antibiotics are discontinued, and the gut microbiota slowly starts to grow back.

The parallel recoveries of the immune system and the microbiota, both of which are damaged and then restored, gives us a unique opportunity to analyze the associations between these two systems, Dr. Schluter says.

For more than ten years, members of MSKs BMT service have regularly collected and analyzed blood and fecal samples from patients throughout the BMT process. The bacterial DNA were processed by the staff at MSKs Lucille Castori Center for Microbes, Inflammation, and Cancer, which played a key role in creating the massive microbiota dataset. Our study shows that we can learn a lot from stool biological samples that literally would be flushed down the toilet, Dr. Xavier notes. The result of collecting them is that we have a unique dataset with thousands of datapoints that we can use to ask questions about the dynamics of this relationship.

This wider effort has been led by Marcel van den Brink, Head of the Division of Hematologic Malignancies, and a team of infectious disease specialists, BMT doctors, and scientists. For a fair number of patients, we collected daily samples so we could really see what was happening day to day, Dr. van den Brink says. The changes in the microbiota are rapid and dramatic, and there is almost no other setting in which you would be able to see them.

Our study shows that we can learn a lot from stool biological samples that literally would be flushed down the toilet.

Previous research using samples collected from this work has looked at how the gut microbiota affects patients health during the BMT process. A study published in February 2020 reported that having a greater diversity of species in the intestinal microbiota is associated with a lower risk of death after a BMT. It also found that having a lower diversity of microbiota before transplant resulted in a higher incidence of graft-versus-host disease, a potentially fatal complication in which the donor immune cells attack healthy tissue.

The databank that the MSK team created contains details about the types of microbes that live in the patients guts at various times. The computational team, including Drs. Schluter and Xavier, then used machine learning algorithms to mine electronic health records for meaningful data. The data from the health records included the types of immune cells present in the blood, information about the medications that patients were given, and the side effects patients experienced. This research could eventually suggest ways to make BMTs safer by more closely regulating the microbiota, Dr. van den Brink says.

Analyzing this much data was a huge undertaking. Dr. Schluter, who at the time was a postdoctoral fellow in Dr. Xaviers lab, developed new statistical techniques for this. Because experiments with people are often impossible, we are left with what we can observe, Dr. Schluter says. But because we have so many data collected over a period of time when the immune system of patients as well as the microbiome shift dramatically, we can start to see patterns. This gives us a good start toward understanding the forces that the microbiota exerts on the rebuilding of the immune system.

This research could eventually suggest ways to make BMTs safer by more closely regulating the microbiota.

The purpose of this study was not to say whether certain kinds of microbes are good or bad for the immune system, Dr. Xavier explains, adding that this will be a focus of future research. Its a complicated relationship. The subtypes of immune cells we would want to increase or decrease vary from day to day, depending on what else is going on in the body. Whats important is that now we have a way to study this complex ecosystem.

The researchers say they also plan to apply their data to studying the immune system in patients receiving other cancer treatments.

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MSK Study Is the First to Link Microbiota to Dynamics of the Human Immune System - On Cancer - Memorial Sloan Kettering

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Global Stem Cell Banking Market to Get Expansion admist COVID 19, Scope With Advanced Technologies Top Key Players and Forecast 2020-2027 – The…

By daniellenierenberg

Databridgemarketresearch.com Present Global Stem Cell Banking Market Industry Trends and Forecast to 2027 new report to its research database. The report spread No of pages: 350 No of Figures: 60 No of Tables: 220 in it. This Global Stem Cell Banking Market report takes into consideration diverse segments of the market analysis that todays business ask for. The Global Stem Cell Banking Market report provides estimations of CAGR values, market drivers and market restraints about the industry which are helpful for the businesses in deciding upon numerous strategies. The base year for calculation in the report is taken as 2017 whereas the historic year is 2016 which will tell you how the Global Stem Cell Banking Market is going to perform in the forecast years by informing you what the market definition, classifications, applications, and engagements are. The report helps you to be there on the right track by making you focus on the data and realities of the industry.

The research studies of this Global Stem Cell Banking Market report helps to evaluate several important parameters that can be mentioned as investment in a rising market, success of a new product, and expansion of market share. Market estimations along with the statistical nuances included in this market report give an insightful view of the market. The market analysis serves present as well as future aspects of the market primarily depending upon factors on which the companies contribute in the market growth, crucial trends and segmentation analysis. This Global Stem Cell Banking Market research report also gives widespread study about different market segments and regions.

Global stem cell banking market is set to witness a substantial CAGR of 11.03% in the forecast period of 2019- 2026. The report contains data of the base year 2018 and historic year 2017. The increased market growth can be identified by the increasing procedures of hematopoietic stem cell transplantation (HSCT), emerging technologies for stem cell processing, storage and preservation. Increasing birth rates, awareness of stem cell therapies and higher treatment done viva stem cell technology.

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Competitive Analysis:

Global stem cell banking market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of inflammatory disease drug delivery market for Global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.

Key Market Competitors:

Few of the major competitors currently working in global inflammatory disease drug delivery market are: NSPERITE N.V, Caladrius, ViaCord, CBR Systems, Inc, SMART CELLS PLUS, LifeCell International, Global Cord Blood Corporation, Cryo-Cell International, Inc., StemCyte India Therapeutics Pvt. Ltd, Cordvida, ViaCord, Cryoviva India, Vita34 AG, CryoHoldco, PromoCell GmbH, Celgene Corporation, BIOTIME, Inc., BrainStorm Cell Therapeutics and others

Market Definition:Global Stem Cell Banking Market

Stem cells are cells which have self-renewing abilities and segregation into numerous cell lineages. Stem cells are found in all human beings from an early stage to the end stage. The stem cell banking process includes the storage of stem cells from different sources and they are being used for research and clinical purposes. The goal of stem cell banking is that if any persons tissue is badly damaged the stem cell therapy is the cure for that. Skin transplants, brain cell transplantations are some of the treatments which are cured by stem cell technique.

Cord Stem Cell Banking MarketDevelopment and Acquisitions in 2019

In September 2019, a notable acquisition was witnessed between CBR and Natera. This merger will develop the new chances of growth in the cord stem blood banking by empowering the Nateras Evercord branch for storing and preserving cord blood. The advancement will focus upon research and development of the therapeutic outcomes, biogenetics experiment, and their commercialization among the global pharma and health sector.

Cord Stem Cell Banking MarketScope

Cord Stem Cell Banking Marketis segmented on the basis of countries into U.S., Canada and Mexico in North America, Germany, France, U.K., Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific (APAC) in the Asia-Pacific (APAC), Saudi Arabia, U.A.E, South Africa, Egypt, Israel, Rest of Middle East and Africa (MEA) as a part of Middle East and Africa (MEA), Brazil, Argentina and Rest of South America as part of South America.

All country based analysis of the cord stem cell banking marketis further analyzed based on maximum granularity into further segmentation. On the basis of storage type, the market is segmented into private banking, public banking. On the basis of product type, the market is bifurcated into cord blood, cord blood & cord tissue. On the basis of services type, the market is segmented into collection & transportation, processing, analysis, storage. On the basis of source, market is bifurcated into umbilical cord blood, bone marrow, peripheral blood stem, menstrual blood. On the basis of indication, the market is fragmented into cerebral palsy, thalassemia, leukemia, diabetes, autism.

Cord stem cell trading is nothing but the banking of the vinculum plasma cell enclosed in the placenta and umbilical muscle of an infant. This ligament plasma comprises the stem blocks which can be employed in the forthcoming time to tackle illnesses such as autoimmune diseases, leukemia, inherited metabolic disorders, and thalassemia and many others.

Market Drivers

Increasing rate of diseases such as cancers, skin diseases and othersPublic awareness associated to the therapeutic prospective of stem cellsGrowing number of hematopoietic stem cell transplantations (HSCTs)Increasing birth rate worldwide

Market Restraint

High operating cost for the therapy is one reason which hinders the marketIntense competition among the stem cell companiesSometimes the changes are made from government such as legal regulations

Key Pointers Covered in the Cord Stem CellBanking MarketIndustry Trends and Forecast to 2026

Market SizeMarket New Sales VolumesMarket Replacement Sales VolumesMarket Installed BaseMarket By BrandsMarket Procedure VolumesMarket Product Price AnalysisMarket Healthcare OutcomesMarket Cost of Care AnalysisMarket Regulatory Framework and ChangesMarket Prices and Reimbursement AnalysisMarket Shares in Different RegionsRecent Developments for Market CompetitorsMarket Upcoming ApplicationsMarket Innovators Study

Key Developments in the Market:

In August, 2019, Bayer bought BlueRock for USD 600 million to become the leader in stem cell therapies. Bayer is paying USD 600 million for getting full control of cell therapy developer BlueRock Therapeutics, promising new medical area to revive its drug development pipeline and evolving engineered cell therapies in the fields of immunology, cardiology and neurology, using a registered induced pluripotent stem cell (iPSC) platform.In August 2018, LifeCell acquired Fetomed Laboratories, a provider of clinical diagnostics services. The acquisition is for enhancement in mother & baby diagnostic services that strongly complements stem cell banking business. This acquisition was funded by the internal accruals which is aimed to be the Indias largest mother & baby preventive healthcare organization.

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Research objectives

To perceive the most influencing pivoting and hindering forces in Cord Stem Cell Banking Market and its footprint in the international market.Learn about the market policies that are being endorsed by ruling respective organizations.To gain a perceptive survey of the market and have an extensive interpretation of the Cord Stem Cell Banking Market and its materialistic landscape.To understand the structure of Cord Stem Cell Banking Market by identifying its various sub segments.Focuses on the key global Cord Stem Cell Banking Market players, to define, describe and analyze the sales volume, value, market share, market competition landscape, SWOT analysis and development plans in next few years.To analyze competitive developments such as expansions, agreements, new product launches, and acquisitions in the market.To share detailed information about the key factors influencing the growth of the market (growth potential, opportunities, drivers, industry-specific challenges and risks).To project the consumption of Cord Stem Cell Banking Market submarkets, with respect to key regions (along with their respective key countries).To strategically profile the key players and comprehensively analyze their growth strategiesTo analyze the Cord Stem Cell Banking Market with respect to individual growth trends, future prospects, and their contribution to the total market.

Customization of the Report:

All segmentation provided above in this report is represented at country levelAll products covered in the market, product volume and average selling prices will be included as customizable options which may incur no or minimal additional cost (depends on customization)

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Global Stem Cell Banking Market to Get Expansion admist COVID 19, Scope With Advanced Technologies Top Key Players and Forecast 2020-2027 - The...

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Stem Cell Therapy Market To Observe Exponential Growth By 2020-2027 | Reports Globe – Cheshire Media

By daniellenierenberg

Fort Collins, Colorado The Stem Cell Therapy Market 2020 Research Report provides information on the market size, share, trends, growth, competitive landscape, challenges and opportunities, revenue, and forecast to 2027. Reports Globe recently incorporated a comprehensive overview of the Stem Cell Therapy market into its extensive database. The Stem Cell Therapy Market report has been aggregated by collecting informative data on various dynamics such as market drivers, restraints, and opportunities.

This innovative report uses SWOT, PESTLE, and Porters Five Forces analysis to get a deeper look at the Stem Cell Therapy market.

Global Stem Cell TherapyMarketwas valued at 117.66 million in 2019 and is projected to reach USD255.37 million by 2027, growing at a CAGR of 10.97% from 2020 to 2027.

Impact of Covid-19 on this Market:

The coronavirus pandemic (COVID-19) has affected all aspects of life around the world. The study provides a comprehensive overview of the impact of the COVID-19 pandemic on the Stem Cell Therapy market and its key segments. It also covers the current and future impact of the pandemic and offers a post-COVID-19 scenario to provide a deeper understanding of the dynamic changes in market trends and scenarios.

Competitive Landscape:

Competitive Analysis is one of the best sections of the report, comparing the progress of leading companies using key metrics like market share, new developments, global reach, local competition, pricing, and production. . From the nature of the competition to future changes in the vendor landscape, the report offers an in-depth competitive analysis in the global Stem Cell Therapy Market.

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Market Segments and Sub-segments Covered in the Report are as per below:

1.Stem Cell Therapy Market, By Cell Source:

Adipose Tissue-Derived Mesenchymal Stem Cells Bone Marrow-Derived Mesenchymal Stem Cells Cord Blood/Embryonic Stem Cells Other Cell Sources

2.Stem Cell Therapy Market, By Therapeutic Application:

Musculoskeletal Disorders Wounds and Injuries Cardiovascular Diseases Surgeries Gastrointestinal Diseases Other Applications

3.Stem Cell Therapy Market, By Type:

Allogeneic Stem Cell Therapy Market, By Application Musculoskeletal Disorders Wounds and Injuries Surgeries Acute Graft-Versus-Host Disease (AGVHD) Other Applications Autologous Stem Cell Therapy Market, By Application Cardiovascular Diseases Wounds and Injuries Gastrointestinal Diseases Other Applications

Research Methodology:

Reports Globe follows a comprehensive research methodology to provide the most accurate market analysis. The company relies on a data triangulation model that can be used to assess market dynamics and provide accurate estimates. Key elements of the research methodology used for all of our market reports include:

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In addition, Reports Globe has access to a wide range of reputable regional and global paid databases that help the company understand regional and global market trends and dynamics. The company analyzes the industry from a 360-degree perspective, i.e. H. From the supply and demand side, which allows us to provide detailed information about the entire ecosystem for each study. Finally, a top-down and bottom-up approach is taken to get the final search results.

It includes analysis on the following

Finally, the Stem Cell Therapy Market Report is a credible source of market research that will accelerate your business exponentially. The report gives the most important regional framework conditions, economic situations with item value, advantage, limit, production, supply, demand, market development rate and number, etc. Stem Cell Therapy Industry Report Also includes a new SWOT review task, speculative test research, and corporate return on investment research.

To learn more about the report, visit @ https://reportsglobe.com/product/global-stem-cell-therapy-market/

Thanks for reading this article; you can also get individual chapter wise section or region wise report versions like North America, Europe, or Asia.

How Reports Globe is different than other Market Research Providers

The inception of Reports Globe has been backed by providing clients with a holistic view of market conditions and future possibilities/opportunities to reap maximum profits out of their businesses and assist in decision making. Our team of in-house analysts and consultants works tirelessly to understand your needs and suggest the best possible solutions to fulfill your research requirements.

Our team at Reports Globe follows a rigorous process of data validation, which allows us to publish reports from publishers with minimum or no deviations. Reports Globe collects, segregates, and publishes more than 500 reports annually that cater to products and services across numerous domains.

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Stem Cell Therapy Market To Observe Exponential Growth By 2020-2027 | Reports Globe - Cheshire Media

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The Stem Cell Characterization and Analysis Tools Market to grow incomparably in the next decade – The Market Feed

By daniellenierenberg

Stem cell characterization is the study of tissue-specific differentiation. Thera are various type of stem cell such as embryonic stem cell, epithelial stem cell and others. Further, various techniques are used to characterized stem cells such as immunological techniques, used for depiction of different population of stem cells. These techniques are generally based on immunochemistry using staining technique or florescent microscopy. Besides, stem cells characterization and analysis tools are used against target chronic diseases. In 2014, the San Diego (UCSD) Health System and Sanford Stem Cell Clinical Center at the University of California announced the launch of a clinical trial, in order to assess the safety of neural stem cellbased therapy in patients with chronic spinal cord injury.

The factors driving the growth of stem cell characterization and analysis tools market due to increasing chronic disorders such as cancer, a diabetes and others. In addition, increasing awareness about among people about the therapeutic potency of stem cells characterization in the management of effective diseases is anticipated to increase the demand for stem cell characterization and analysis tools. Further, there are various technologies such as flow cytometry which is used to characterize the cell surface profiling of human-bone marrow and other related purposes are expected to increase the growth of stem cell characterization and analysis tools market. In addition, increasing investment by private and public organization for research activities are likely to supplement the market growth in near future.

On the other hand, the unclear guidelines and the technical limitation for the development of the product are expected to hamper the growth of stem cell characterization and analysis tools market.

Rapid increase in corona virus all around the world is expected to hamper the growth of stem cell characterization and analysis tools market. The virus outburst has become one of the threats to the global economy and financial markets. The impact has made immense decrease in revenue generation in the field of all healthcare industry growth for the market in terms of compatibility and it has led in huge financial losses and human life which has hit very hard to the core of developing as well as emerging economies in healthcare sector. It further anticipated that such gloomy epidemiological pandemic environment is going to remain in next for at least some months, and this is going to also affect the life-science market which also include the market of stem cell characterization and analysis tools market.

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Based on the Products and Service Type, stem cell characterization and analysis tools market are segmented into:

Based on the Technology, stem cell characterization and analysis tools market are segmented into:

Based on the Applications, stem cell characterization and analysis tools market are segmented into:

Based on the End User, stem cell characterization and analysis tools market are segmented into:

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Based on the segmentation, human embryonic stem cell is expected to dominate the market due to their indefinite life span and higher totipotency as compared to other stem cells. Further, on the basis of technology segmentations, cell production is anticipated to increase the demand for stem cell characterization and analysis tools due to their emerging applications for stem cells in drug testing in the management of the effective diseases. Furthermore, on the basis of application segmentations, oncology is expected to show significant growth rate due to increase in the number of pipelines products for the treatment of cancers or tumors. Based on the end user, pharmaceutical and biotechnology companies are expected to dominate the market due to rising global awareness about the therapeutics research activities.

Geographically, the global stem cell characterization and analysis tools market is segmented into regions such as Latin America, Europe, North America, South Asia, East Asia Middle East & Africa and Oceania. North America is projected to emerge as prominent market in the global stem cell characterization and analysis tools market due to growing cases of target chronic diseases and increasing investments for research activities. Europe is the second leading region to dominate the market due to technological advancement and also surge in therapeutic activities, funded by government across the world. Asia-pacific is likely to witness maximum growth in near future due to increasing disposable income and with the development of infrastructure.

Some of the major key players competing in the global stem cell characterization and analysis tools market are Osiris Therapeutics, Inc., Caladrius Biosciences, Inc., U.S. Stem Cell, Inc., Astellas Pharma Inc., TEMCELL Technologies Inc., BioTime Inc., Cellular Engineering Technologies Inc., Cytori Therapeutics, Inc., and BrainStorm Cell Therapeutics Inc.

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To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

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Easton Lindeman gets a visit from the Pink Fire Truck – News – vintontoday.com

By daniellenierenberg

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This past February, Easton Lindeman then age 2, son ofCorey and Samantha was diagnosed with high-risk neuroblastoma, a type of cancer that affects his adrenal glands, spinal column, and bone marrow.Neuroblastoma is a cancer that develops from immature nerve cells found in several areas of the body. Treatment for Easton started right away. This was followed by hospitalizations for both treatments and illnesses. So far he has gone through 3 rounds of chemotherapy and IMIBG therapy at the University of Wisconsin. IMIBG Therapy is a form of radiation treatment. This was followed by more chemotherapy and surgery to try to remove as much of the tumor as possible.

The last time we talked with Easton's mom he was finishing up with his 6th round of high dose chemotherapy and stem cell transplant.

He has had countless blood and platelet transfusions, ECHO's, hearing tests, MRI's, CT scans, X-Rays, bone marrow biopsies, surgeries and sedations. PICC line placements and Port Access placement. Earlier this month, Easton took a trip to the Mayo Clinic for more treatment.

On Saturday, Easton had a very special treat. The pink firetruck, overseen by Dennis and Diana Brammow made a stop to see Easton.

Easton is 3 years old now and his mom said that he loves to pass out candy to the doctors in and nurse friends while he's in the hospital. Like most 3 year old, there isn't a lot that slows him down. At 3 he's a family man already. Tagging around after his big brother Hunter and cousin Eleanor and he's always thrilled to visit his Grandpa and Grandma Dough and Dawn Yenser.

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Easton Lindeman gets a visit from the Pink Fire Truck - News - vintontoday.com

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The Stem Cell-Derived Cells Market to witness explicit growth from 2019 and 2029 – The Haitian-Caribbean News Network

By daniellenierenberg

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

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The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

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North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

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Explore Extensive Coverage of PMR`s

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About us:

Persistence Market Research (PMR) is a third-platform research firm. Our research model is a unique collaboration of data analytics andmarket research methodologyto help businesses achieve optimal performance.

To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

Contact us:

Naved BegPersistence Market ResearchAddress 305 Broadway, 7th Floor, New York City,NY 10007 United StatesU.S. Ph. +1-646-568-7751USA-Canada Toll-free +1 800-961-0353Sales[emailprotected]Websitehttps://www.persistencemarketresearch.com

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The Stem Cell-Derived Cells Market to witness explicit growth from 2019 and 2029 - The Haitian-Caribbean News Network

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