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Global Autologous Stem Cell Based Therapies Market 2020 Key Drivers and Restraints, Regional Outlook, End-User Applicants by 2025 – The Pinstripe…

By daniellenierenberg

Global Autologous Stem Cell Based Therapies Market 2020 by Company, Type and Application, Forecast to 2025 has been updated by MarketsandResearch.biz replete with a precise analysis of the market, specifically that approach market size, trends, share, outlook, production, and futuristic development trends and present and future market status from 2020 to 2025. The report comprises of a comprehensive investigation into the geographical landscape, industry size along with the revenue estimation of the business. The report supplies a point by point analysis dependent on the exhaustive research of the global Autologous Stem Cell Based Therapies market elements like development situation, potential opportunities, and operation landscape and trend analysis. The study recognizes the factors behind the growth of certain segments and focuses on business models expected to create new revenue for market players. The report also offers insight into emerging trends and restraints.

About Manufacturers And Growing Competition:

The report highlights crucial details on specific areas comprising a detailed analytical review of the competition spectrum. Each of the leading players is thoroughly identified and profiled in the global Autologous Stem Cell Based Therapies report with their product portfolio as well as company status and portfolio. The report is a complete representation of all the major initiatives initiated by various market players across diverse geographical areas. After studying key companies, the report focuses on the new entrants contributing to the growth of the market.

NOTE: Our report highlights the major issues and hazards that companies might come across due to the unprecedented outbreak of COVID-19.

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Some players from complete research coverage: Regeneus, US STEM CELL, INC., Mesoblast, Med cell Europe, Pluristem Therapeutics Inc, Tigenix, Brainstorm Cell Therapeutics

This report segments on the basis of types are: Embryonic Stem Cell, Resident Cardiac Stem Cells, Umbilical Cord Blood Stem Cells

This report segments on the basis of application are: Neurodegenerative Disorders, Autoimmune Diseases, Cardiovascular Diseases

For a comprehensive understanding of market dynamics, the global Autologous Stem Cell Based Therapies market analyzed across key geographies namely: North America (United States, Canada and Mexico), Europe (Germany, France, United Kingdom, Russia and Italy), Asia-Pacific (China, Japan, Korea, India, Southeast Asia and Australia), South America (Brazil, Argentina), Middle East & Africa (Saudi Arabia, UAE, Egypt and South Africa)

The study then investigates the important achievements of the market, Research & Development, new product launch, product responses, and regional growth of the most important competitors operating in the global Autologous Stem Cell Based Therapies market. The analysis also takes into account the existing and upcoming technological aspects of the market. Finally, the report describes the sales channel, distributors, traders, dealers, research findings and Conclusion, appendix, and data source. The data about producing base distribution, sales area, product kind, market competitive scenario, and trends, market concentration rate has been given further.

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Global Autologous Stem Cell Based Therapies Market 2020 Key Drivers and Restraints, Regional Outlook, End-User Applicants by 2025 - The Pinstripe...

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Eye stem cell transplant to treat blindness bolsters retinal function in monkeys – FierceBiotech

By daniellenierenberg

Retinal cell transplants are considered to be an attractive approach for treating blindness. Question is, where do you source the cells?

An international research team of scientists from Singapores Agency for Science, Technology and Research (A*STAR), the Icahn School of Medicine at Mount Sinai in New York and Germanys Eye Clinic Sulzbach is using a type of stem cell in the eye to grow the pigmented layer of retina thats essential for vision. The approach is showing promise in monkeys.

The findingssuggest that these retinal pigment epithelium (RPE) stem cell-derived RPE, or hRPESC-RPE, may be a useful source for cell replacement therapies to treatRPE-related blindness caused by diseases such as macular degeneration, the researchers suggest. The results are published in the journal Stem Cell Reports.

RPE is a layer of tissue that supports the neurosensory retina and is critical for vision. An estimated 200 million people live with diseases associated with RPE dysfunction, including macular degeneration. Early attempts at RPE replacement used cells from the patientan approach with limitationsscientists have been searching for treatment using different populations of stem cells.

In 2012, scientists identified a type of adult cell in the RPE that's normally dormant but that can be activated to take on a stem-cell-like state with self-renewing ability. These cells have the potential to differentiate into RPE cells and could therefore be used for RPE replacement therapies, the A*STAR-led team figured.

In their study, the researchers took hRPESC-RPE from donated adult eyes and grew them into RPE monolayers. When transplanted into the eyes of monkeys on a polymer scaffold, theRPE patches stably integrated for at least three months.

The stem cell-derived RPE patchespartially took over and were able to support normal light-sensing function, the team showed. Whats more, the method didnt cause vision-blocking retinal scarring that has been seen with other experimental approaches.

RELATED:Reprogrammed skin cells restore sight in mouse models of retinal disease

Multiple types of stem cells, includinghuman embryonic stem cells and human-induced pluripotent stem cells, have been proposed as alternative sources for retinal replacement. A team led by Mount Sinai previously used gene transfer to activate a type of retinal cells called Mller glial to adopt stem-cell-like characteristics. The team prompted the cells to divide into light-sensing rod photoreceptor cells in blind mice.

Researchers led by the National Institutes of Healths National Eye Institute used five chemicals to turn skin cells directly into rod photoreceptors.

The A*STAR-led researchers believetheir study demonstrates the potential of using hRPESC-RPE transplants as a treatment for macular degeneration. Further studies are needed to test the method in monkey models of eye disease to gauge the therapeutic effect, the researcher suggested.

If the cells succeed, they could serve as an unlimited resource for human RPE. Because the cells are harvested from human eyes, the researchers suggested establishing hRPESC-RPE donor banks to provide cells that match individual patients so there is noimmune rejection.

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Seattle researchers find clues for treatments that could eliminate HIV in infected patients – GeekWire

By daniellenierenberg

Dr. Joshua Schiffer (third from left) and E. Fabian Cardozo-Ojeda (far right) led research published on Tuesday that provides mathematical models on strategies for optimizing treatment for HIV. (Fred Hutchinson Cancer Research Center Photo)

In the nearly four decades since HIV was discovered, only two people have been cured of the virus that has killed millions.

Researchers in Seattle are hoping to boost that number. On Tuesday, scientists from the Fred Hutchinson Cancer Research Center and the University of Washington published a study that provides clues to optimizing treatments that could wipe out HIV in infected patients.

Worldwide, some 26 million people are receiving antiviral therapy to keep the virus in check, but the drugs dont completely stamp out HIV, the virus that causes AIDS. The virus becomes latent, hiding out in cells until the drugs are gone. It gets activated again and starts reproducing.

One key component to HIVs reanimation is the presence of a molecule called CCR5 thats found on the outside of a certain class of immune system cells. The CCR5 helps the virus enter and infect new cells.

The two men seemingly cured of HIV, known as the Berlin Patient and the London Patient, also had cancer, one with acute myeloid leukemia and the other Hodgkin Lymphoma. As part of their cancer treatments, the patients received transplants of healthy stem cells, which produce immune system cells. They received the transplants from donors who lacked the gene that produces functional CCR5 molecules.

It appears that by suppressing the virus and then cutting off its pathway to resurgence, the virus can be defeated.

Since the 1960s, the Fred Hutch has been a pioneer in bone marrow transplants in cancer treatment, and researchers there are applying similar strategies for treating HIV.

Fred Hutch and UW scientists in recent years have performed experiments using pig-tailed macaques that are infected with a simian version of HIV. In one study of 22 monkeys, the infected macaques received transplants of their own stem cells, after they were treated to knock out the CCR5 gene. Researchers were interested in using the monkeys own altered cells because their immune systems would accept them and not perceive them as foreign invaders to be fought off.

One of the challenges of this approach to fighting HIV is figuring out how many of the altered stem cells are needed its difficult to produce a massive supply in order to overwhelm the cells that still produce CCR5. Add to that the rate of stem cell replication and figuring out the timing of administering and stopping antiviral drugs.

Thats where the new research comes in.

E. Fabian Cardozo-Ojeda, a senior staff scientist at the Fred Hutchs Vaccine and Infectious Disease Division, took all of the data available from the 22 monkeys to figure out how to perfect the treatment. He and his team developed a multi-stage mathematical model to calculate the effects of different amounts of residual and transplanted stem cells, the HIV viral load and the timing of when antiviral drugs are halted.

Were trying to do interdisciplinary work to get that optimal approach for a cure, Cardozo-Ojeda said.

In order to control HIV through this strategy, the researchers came to two conclusions with their formula. First, a patient needs a dose of at least five times as many transplanted stem cells compared to residual cells, and second, before a patient stops taking antiviral drugs, the cells lacking CCR5 need to total between 76-to-94% of the total transplanted stem cell population in their blood.

While the study was based on macaque data, were generating possible hypotheses of what could happen with people, Cardozo-Ojeda said. When it comes to applying their formula to higher primates, we believe that could be translated to humans for sure.

The peer-reviewed study was published by eLife, a non-profit platform. Cardozo-Ojeda is first author of the study and the other authors are Elizabeth Duke, Christopher Peterson, Daniel Reeves, Bryan Mayer, Hans-Peter Kiem and Joshua Schiffer.

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Reversing The Aging Clock With Epigenetic Reprogramming – Bio-IT World

By daniellenierenberg

By Deborah Borfitz

January 13, 2021 | As aging researchers are aware, birthday candles are not a good guide to either human health or longevity. But there is an abundance of clues in the genome and, as suggested by studies in animals, some of age-related damage is reversible by removing or reprogramming problematic cells or blocking the activity of key proteins.

As it turns out, DNA methylationa frequently-used biomarker of biological ageis not just marking time like a clock on the wall but actually controlling time within cells, according to David Sinclair, an expert on aging at Harvard Medical School and cofounder of 4-year-old Life Biosciences. The revelation emerged from a study recently published in Nature (DOI: 10.1038/s41586-020-2975-4) where Harvard researchers showed, for the first time, that the pattern of DNA methylation in the genome can be safely reset to a younger age.

It was in fact a prerequisite to restoring youthful function and vision in old mice, says Sinclair, who has spent most of his adult life studying the epigenetic changes associated with aging. Up until a few years ago, he thought the process was unidirectional and that cells ultimately lost their identity and malfunctioned or became cancerous.

It seemed crazy to try to get proteins to return to the place they were in young cells, Sinclair says. Proteins move around in response to age-associated DNA damage and end up in the wrong places on the genome, causing the wrong genes to be turned on, but scientists did not know if proteins could go back, where the instructions were stored, or if they were being stored at all.

As covered in his 2019 bestseller Lifespan, Sinclair now believes that aging is the result of the so-called epigenetic changes scrambling how the body reads genetic code. Were essentially looking for the polish to get the cell to read the genome correctly again, he says, a process he likens to recovering music on a scratched CD.

Yamanaka Factors

Sinclair and his research associates have been focusing on the eye, in part because retinal tissues start aging soon after birth, he explains. While a damaged optic nerve can heal in a newborn, the injury is irreversible in a 1-year-old.

Yuancheng Lu, a former student of Sinclairs, was also interested in the eye because his family has a vision-correction business and recognized sight loss as a huge unmet need, he continues. We thought if we could take the age of those retinal cells back far enough, but not so far that they lose their identity, we might be able to see regrowth of the optic nerve if it was damaged.

Among the foundational work was a 2016 study in Cell (DOI: 10.1016/j.cell.2016.11.052) by Life Biosciences cofounder Juan Carlos Izpisua Belmonte (Salk Institute for Biological Studies) who partially erased cellular markers of aging in mice that aged prematurely, as well as in human cells, by turning on Yamanaka factors Oct4, Sox2, Klf4, and c-Myc (OSKM) highly expressed in embryonic stem cells. Short-term induction of OSKM ameliorated hallmarks of aging and modestly extended lifespan in the short-lived mice.

The lifespan gain was widely dismissed as an artifact of shocking a mouse, says Sinclair, since the mice died if the treatment continued for more than two days. Although the human health implications appeared unlikely, his Harvard team decided to try the approach using an adeno-associated virus as a vehicle to deliver the youth-restoring OSKM genes into the retinas of aging mice.

The technology kept killing the mice or causing them to get cancer until Lu decided to drop the c-Myc genean oncogenein his experiments using human skin cells. He looked at [damaged] cells that had been expressing OSK for three weeks and the nerves were growing back toward the brain to an unprecedented degree. Moreover, the cells got older by the damage and younger by the treatment.

As the broader team went on to show in the Nature paper, the trio of Yamanaka factors effectively made cells younger without causing them to lose their identity (i.e., turning back into induced pluripotent stem cells) or fueling tumor growth even after a year of continuous treatment of the entire body of a mouse. If anything, the mice had fewer tumors over the course of the study, says Sinclair.

Although the mice needed to be autopsied to definitively measure tumor burden, Sinclair says the study will be repeated to learn if the epigenetic reprogramming technique can increase lifespan.

Findings have implications beyond the treatment of age-related diseases specific to the eye, says Sinclair. Aging researchers have published studies showing other types of tissues, including muscle and kidney cells, can also be rejuvenated.

Clocked Results

In the latest study using mice, epigenetic reprogramming was found to have three beneficial effects on the eye: promotion of optic nerve regeneration, reversal of vision loss with a condition mimicking human glaucoma, and reversal of vision loss in aging animals without glaucoma. The latter finding, from Sinclairs vantage point, is the most important one. This is ultimately a story about finding a repository of youthful information in old cells that can reverse aging.

Results of all three experiments are noteworthy and have commonly thought to be three separate processes, says Sinclair. That is only because the fields of aging and acute and chronic disease are distinct disciplines that rarely talk to each other.

The Harvard team is pioneering a new way to tackle diseases of aging by addressing the underlying cause. This is the first time, as far as Sinclair is aware, where nerve damage was studied in old rather than young animals. In the case of glaucoma and most diseases, aging is considered largely irrelevant, when of course we know glaucoma is a disease of aging.

A variety of aging clocks, including some the research team built themselves, have been deployed for studies because they are considered the most accurate predictor of biological age and future health, says Sinclair. As embryos, cells lay down different patterns of methylation to ensure they remember their purpose over the next 80 to 100 years.

For unknown reasons, methyl groups get predictably added and subtracted from DNA bases across cell and tissue types and even species, Sinclair says. In 2013, UCLAs Steve Horvath (another Life Biosciences cofounder) showed that machine learning could be used to pick out the hot spots and predict individual lifespan depending on how far above or below the DNA methylation line they sit (Genome Biology, DOI: 10.1186/gb-2013-14-10-r115).

A multitude of aging clocks have since been developed. Eventually, we will need some standardization in the field, but there is nothing super-mysterious about aging clocks, says Sinclair. One of my grad students could probably get you one by the end of the day.

Booming Field

Aging research is a rapidly accelerating field and epigenetic reprogramming is poised to become a particularly active area of inquiry. In terms of numbers, there are still only a dozen or so labs intensely working on this, but there are probably a hundred others I am aware of who are getting into it, says Sinclair.

Life Biosciences began with four labs, but new ones are now joining on an almost weekly basis, he adds. Collaborators have expanded work to the ear and other areas of the body beyond the eye, he adds.

Were also reducing the cost of the DNA clock test by orders of magnitude so [biological age prediction] can be done on millions of people, he continues. In the future, aging clocks are expected to be a routine test in physicians arsenal to guide patient care as well as to monitor response to cancer treatment.

Harvard University has already licensed two patents related to the technology used by the aging researchers to Life Biosciences, Sinclair says. The company has built a scientific team with a group of world-class advisors who developed gene therapy for the eye, which will be tested first for the treatment of glaucoma.

The role of chaperone-mediated autophagy in aging and age-related diseases is another promising area of research being pursued by Life Biosciences Ana Maria Cuervo, M.D, Ph.D., professor, and co-director of the Institute of Aging Studies at the Albert Einstein College of Medicine. Cuervo recently reported at a meeting that fasting-induced autophagy, the cells natural mechanism for removes unnecessary or dysfunctional components, can greatly extend the lifespan of mice. She believes the triggering of this process might one day help treat diseases such as macular degeneration and Alzheimers.

The specialty of Manuel Serrano, Ph.D., the fourth company cofounder, is cellular senescence and reprogramming and how they relate to degenerative diseases of the lung, kidney, and heart. He isan internationally recognized scientist who has made significant contributions to cancer and aging research and works in the Institute for Research Biomedicine in Barcelona.

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Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy – DocWire News

By daniellenierenberg

This article was originally published here

Stem Cell Res Ther. 2021 Jan 13;12(1):58. doi: 10.1186/s13287-020-02110-x.

ABSTRACT

INTRODUCTION: Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease (PAD) characterized by ischemic rest pain and non-healing ulcers. Currently, the standard therapy for CLI is the surgical reconstruction and endovascular therapy or limb amputation for patients with no treatment options. Neovasculogenesis induced by mesenchymal stem cells (MSCs) therapy is a promising approach to improve CLI. Owing to their angiogenic and immunomodulatory potential, MSCs are perfect candidates for the treatment of CLI. The purpose of this study was to determine and compare the in vitro and in vivo effects of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue mesenchymal stem cells (AT-MSCs) on CLI treatment.

METHODS: For the first step, BM-MSCs and AT-MSCs were isolated and characterized for the characteristic MSC phenotypes. Then, femoral artery ligation and total excision of the femoral artery were performed on C57BL/6 mice to create a CLI model. The cells were evaluated for their in vitro and in vivo biological characteristics for CLI cell therapy. In order to determine these characteristics, the following tests were performed: morphology, flow cytometry, differentiation to osteocyte and adipocyte, wound healing assay, and behavioral tests including Tarlov, Ischemia, Modified ischemia, Function and the grade of limb necrosis scores, donor cell survival assay, and histological analysis.

RESULTS: Our cellular and functional tests indicated that during 28 days after cell transplantation, BM-MSCs had a great effect on endothelial cell migration, muscle restructure, functional improvements, and neovascularization in ischemic tissues compared with AT-MSCs and control groups.

CONCLUSIONS: Allogeneic BM-MSC transplantation resulted in a more effective recovery from critical limb ischemia compared to AT-MSCs transplantation. In fact, BM-MSC transplantation could be considered as a promising therapy for diseases with insufficient angiogenesis including hindlimb ischemia.

PMID:33436054 | DOI:10.1186/s13287-020-02110-x

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Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy - DocWire News

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Shipyard worker Brad Lawson from Walney may have saved a stranger’s life with his stem cell donation – NW Evening Mail

By daniellenierenberg

A SHIPYARD worker has potentially saved a stranger's life after donating his stem cells to a person in desperate need.

Brad Lawson, from Walney, first signed up to be a stem cell donor six years ago after an event at his college.

Stem cells are cells with the potential to develop into many different types of cells in the body.

Every 14 minutes, someone is diagnosed with blood cancer such as leukaemia.

For many, a bone marrow or blood stem cell transplant is their only chance.

They need cells from a healthy person with the same tissue type to replace and repair their own damaged cells.

About 30 per cent of people in need can find a suitable donor in their family but the other 70 per cent rely on a stranger to save their lives.

This is what prompted Mr Lawson to travel hundreds of miles to London to give his much-needed donation.

The 23-year-old said: "I first signed onto the register six years ago and hadn't thought much about it since.

"Then I was shocked to get a phone call the other week to say they'd matched a patient with my stem cells.

"It's quite rare to match with someone - it's only one in 800 people so I knew I had to help."

Mr Lawson travelled down to London where he underwent peripheral blood stem cell collection.

The process involves having a course of injections prior to collection to stimulate the bone marrow and increase the number of stem cells and white blood cells in the blood.

He said: "I had no hesitation about going down there when I got the call. When you sign up, you need to be fully committed if you do get a call.

"This could be someone's chance of survival and I would never pull out of something like that.

"The process was actually really easy. It takes about five hours and isn't painful at all.

"I absolutely hate needles and didn't find it painful at all."

Mr Lawson said it felt 'rewarding' to know his donation could have possibly saved a stranger's life.

"You could potentially give someone the chance to survive by signing up," he said.

"It's an amazing thing to do which could seriously make a difference.

"I may be in that position one day where I desperately need stem cells and would like to think someone out there would help me.

"Donations literally saves lives. It's a really rewarding thing to do to be able to help someone in this way."

Mr Lawson is urging the public to sign up to the register.

"Only about two per cent of people in the UK are actually on the register," he said.

"I'm telling everyone to sign up and raise awareness of stem cell donation.

"The more people we can get to sign up, and save lives, the better."

To register, visit: http://www.dkms.org.uk/en/register-now.

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A Study of Cord Blood Transplantation in Children and Young Adults with Blood Cancers and Non-Cancerous Blood Disorders – On Cancer – Memorial Sloan…

By daniellenierenberg

Full TitleCord Blood Transplantation in Children and Young Adults with Hematologic Malignancies and Non-Malignant DisordersPurpose

The transplantation of stem cells from umbilical cord blood is a treatment for some blood cancers and non-cancerous blood or metabolic disorders. Patients routinely receive high doses of chemotherapy and sometimes radiation before receiving the stem cells to help make room in the bone marrow for new blood stem cells to grow, prevent the body from rejecting the transplanted cells, and help kill any abnormal blood cells in the body. However, the combination of these treatments can have serious side effects.

Researchers are doing this study to find out whether a combination of the chemotherapy drugs clofarabine, fludarabine, and busulfan (without radiation) is a safe and effective treatment for children and young adults receiving cord blood transplants for blood cancers or non-cancerous blood or metabolic disorders. These three drugs are given intravenously (by vein).

To be eligible for this study, patients must meet several criteria, including but not limited to the following:

For more information about this study and to inquire about eligibility, please contact 1-833-MSK-KIDS.

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A Study of Cord Blood Transplantation in Children and Young Adults with Blood Cancers and Non-Cancerous Blood Disorders - On Cancer - Memorial Sloan...

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Adipose Derived Stem Cell Therapy Market Analysis and Forecast, 2020-2026 Coherent Market Insights | BioRestorative Therapies, Inc., Celltex…

By daniellenierenberg

The Adipose Derived Stem Cell Therapy Market Research Report is a resource, which provides current as well as upcoming technical and financial details of the industry to 2027. This report gives you so important and essentials data of Market size, share, trends, Growth, applications, forecast and cost analysis. Delivery development in North America, China, Europe, and South East Asia, Japan as well as in the Globe. The report proves to be indispensable when it comes to market definition, classifications, applications and engagements. The market report also computes the market size and revenue generated from the sales. The industry analysis report presents the key statistics on the market status of global and regional manufacturers and also acts as a valuable source of leadership and direction. What is more, theAdipose Derived Stem Cell Therapy market report analyses and provides historic data along with the current performance of the market

Adipose derived stem cells (ADSCs) are stem cells derived from adipocytes, and can differentiate into variety of cell types. ADSCs have multipotency similar to bone marrow mesenchymal stem cells, thus ADSCs substitute for bone marrow as a source of stem cells. Numerous manual and automatic stem cell separation procedures are adopted in order to separate adipose stem cells (ASCs) from adipose tissue. Flow cytometry can also be used to isolate ADSCs from other stem cells within a cell solution.

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Global Adipose Derived Stem Cell Therapy Market competition by Top Key Players: BioRestorative Therapies, Inc., Celltex Therapeutics Corporation, Antria, Inc., Cytori Therapeutics Inc., Intrexon Corporation, Mesoblast Ltd., iXCells Biotechnologies, Pluristem Therapeutics, Inc., Thermo Fisher Scientific, Inc., Tissue Genesis, Inc., Cyagen US Inc., Celprogen, Inc., and Lonza Group, among others.

Adipose Derived Stem Cell Therapy Market section by Region:

The Middle East and Africa North AmericaSouth AmericaEuropeAsia-Pacific

Segmentation: The report has been separated into different categories, such as product type, application, end user, and region. Every segment is evaluated based on the CAGR, share and growth potential. In the regional analysis, the report highlights the prospective region, which should generate opportunities in the global Adipose Derived Stem Cell Therapy market in the years to come. This segmented analysis will surely prove to be a useful tool for readers, stakeholders and market participants to get a full picture of the Adipose Derived Stem Cell Therapy global market and its growth potential in the years to come.

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Assessment of the COVID-19 impact on the growth of the Adipose Derived Stem Cell Therapy MarketSuccessful market entry strategies formulated by emerging market playersPricing and marketing strategies adopted by established market playersCountry-wise assessment of the Adipose Derived Stem Cell Therapy Market in key regionsYear-on-Year growth of each market segment over the forecast period 2026

TheAdipose Derived Stem Cell TherapyMarket report considers the following years to predict market growth:

The GlobalAdipose Derived Stem Cell TherapyMarket is displayed in 13 Chapters:

Chapter 1: Market Overview, Drivers, Restraints and OpportunitiesChapter 2: Market Competition by ManufacturersChapter 3: Production by RegionsChapter 4: Consumption by RegionsChapter 5: Production, By Types, Revenue and Market share by TypesChapter 6: Consumption, By Applications, Market share (%) and Growth Rate by ApplicationsChapter 7: Complete profiling and analysis of ManufacturersChapter 8: Manufacturing cost analysis, Raw materials analysis, Region-wise manufacturing expensesChapter 9: Industrial Chain, Sourcing Strategy and Downstream BuyersChapter 10: Marketing Strategy Analysis, Distributors/TradersChapter 11: Market Effect Factors AnalysisChapter 12: Market ForecastChapter 13:Adipose Derived Stem Cell Therapy Research Findings and Conclusion, Appendix, methodology and data source

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Adipose Derived Stem Cell Therapy Market Analysis and Forecast, 2020-2026 Coherent Market Insights | BioRestorative Therapies, Inc., Celltex...

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Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma – DocWire News

By daniellenierenberg

This article was originally published here

Cancers (Basel). 2021 Jan 10;13(2):E226. doi: 10.3390/cancers13020226.

ABSTRACT

Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56dim NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression.

PMID:33435153 | DOI:10.3390/cancers13020226

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Bone Therapeutics and Rigenerand sign partnership for cell therapy process development – GlobeNewswire

By daniellenierenberg

Gosselies, Belgium and Modena, Italy, 14January 2021, 7am CET BONE THERAPEUTICS (Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, and Rigenerand SRL, the biotech company that both develops and manufactures medicinal products for cell therapy applications, primarily for regenerative medicine and oncology, today announce the signing of a first agreement for a process development partnership.

Allogeneic mesenchymal stem cell (MSC) therapies are currently being developed at an incredible pace and are evaluated in numerous clinical studies covering diverse therapeutic areas such as bone and cartilage conditions, liver, cardiovascular and autoimmune diseases in which MSCs could have a significant positive effect. Advances in process development to scale up these therapies could have major impacts for both their approval and commercial viability. This will be essential to bring these therapies to market to benefit patients as quickly as possible, said Miguel Forte, CEO, Bone Therapeutics. Hence, whilst Bone Therapeutics is driving on its existing clinical development programs, we have signed a first formal agreement with Rigenerand as a fellow MSC-based organization. This will result in both companies sharing extensive expertise in the process development and manufacturing of MSCs and cell and gene therapy medicinal products. Bone Therapeutics also selected Rigenerand to partner with for their additional experience with wider process development of advanced therapy medicinal products (ATMPs), including the conditioning and editing of MSCs. Rigenerand was founded by Massimo Dominici, a world opinion leader in the cell therapy with an unparalleled MSC expertise and knowledge.

The scope of collaborations between Bone Therapeutics and Rigenerand aims to focus on different aspects of product and process development for Bone Therapeutics expanding therapeutic portfolio. Rigenerand will contribute to improving the processes involved in the development and manufacture of Bone Therapeutics MSC based allogeneic differentiated cell therapy products as they advance towards patients. The first collaboration between the two organizations will initially focus on augmented professional bone-forming cells cells that are differentiated and programmed for a specific task. There is also potential for Bone Therapeutics to broaden its therapeutic targets and explore new mechanisms of action with potential gene modifications for its therapeutic portfolio.

In addition to Rigenerands MSC expertise, Bone Therapeutics also selected Rigenerand as a partner for Rigenerands GMP manufacturing facility. This facility, situated in Modena, Italy, has been designed to host a number of types of development processes for ATMPs. These include somatic, tissue engineered and gene therapy processes. These multiple areas of Rigenerand capabilities enable critical development of new processes and implementation of the gene modification of existing processes. In addition, Rigenerand has built considerable experience in cGMP manufacturing of MSC-based medicinal products, including those that are genetically modified.

Process development and manufacturing is a key part of the development for ATMPs internationally. Navigating these therapies through the clinical development phase and into the market requires a carefully considered process development pathway, said Massimo Dominici, scientific founder, Rigenerand, professor of medical oncology, and former President of the International Society for Cell & Gene Therapy (ISCT). This pathway needs to be flexible, as both the market and materials of these therapies continues to evolve alongside an improved clinical efficacy.

Rigenerand will offer considerable input from its experience of MSC-based therapies to enable Bone Therapeutics to keep and further accelerate the pace in development of the product processes of its MSC based allogeneic differentiated cell therapy as they advance towards patients, said Giorgio Mari, CEO, Rigenerand. We will continue to use our MSC expertise in the development of Rigenerands own products, as well as in process development and manufacturing cell and gene therapies for partner organizations across the globe.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a, diversified portfolio of cell and biologic therapies at different stages ranging from pre-clinical programs in immunomodulation to mid-to-late stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf next-generation improved viscosupplement, JTA-004, which is currently in Phase III development for the treatment of pain in knee osteoarthritis. Consisting of a unique combination of plasma proteins, hyaluronic acid - a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain and inflammation. Positive Phase IIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company has initiated patient recruitment for the Phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

About Rigenerand

Rigenerand SRL is a biotech company that both develops and manufactures medicinal products for cell therapy applications, primarily for regenerative medicine and oncology and 3D bioreactors as alternative to animal testing for pre-clinical investigations.

Rigenerand operates through three divisions:

Rigenerand is developing RR001, a proprietary ATMP gene therapy medicinal product for the treatment of pancreatic ductal adenocarcinoma (PDAC). RR001 has been granted an Orphan Drug Designation (ODD) by US-FDA and from the European Medicine Agency. The Clinical trial is expected to start in Q2 2021.

Rigenerand is headquartered in Medolla, Modena, Italy, with more than 1,200 square metres of offices, R&D and quality control laboratories and a cell factory of 450 square metres of sterile cleanroom (EuGMP Grade-B) with BSL2/BSL3 suites for cell and gene therapies manufacturing. It combines leaders and academics from biopharma and medical device manufacturing sectors.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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Stem Cell Assay Market | Know the aspects that will serve as game-changers for the market – BioSpace

By daniellenierenberg

Stem cell assay refers to the procedure of measuring the potency of antineoplastic drugs, on the basis of their capability of retarding the growth of human tumor cells. The assay consists of qualitative or quantitative analysis or testing of affected tissues and tumors, wherein their toxicity, impurity, and other aspects are studied.

With the growing number of successful stem cell therapy treatment cases, the global market for stem cell assays will gain substantial momentum. A number of research and development projects are lending a hand to the growth of the market. For instance, the University of Washingtons Institute for Stem Cell and Regenerative Medicine (ISCRM) has attempted to manipulate stem cells to heal eye, kidney, and heart injuries. A number of diseases such as Alzheimers, spinal cord injury, Parkinsons, diabetes, stroke, retinal disease, cancer, rheumatoid arthritis, and neurological diseases can be successfully treated via stem cell therapy. Therefore, stem cell assays will exhibit growing demand.

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Another key development in the stem cell assay market is the development of innovative stem cell therapies. In April 2017, for instance, the first participant in an innovative clinical trial at the University of Wisconsin School of Medicine and Public Health was successfully treated with stem cell therapy. CardiAMP, the investigational therapy, has been designed to direct a large dose of the patients own bone-marrow cells to the point of cardiac injury, stimulating the natural healing response of the body.

Newer areas of application in medicine are being explored constantly. Consequently, stem cell assays are likely to play a key role in the formulation of treatments of a number of diseases.

Global Stem Cell Assay Market: Overview

The increasing investment in research and development of novel therapeutics owing to the rising incidence of chronic diseases has led to immense growth in the global stem cell assay market. In the next couple of years, the market is expected to spawn into a multi-billion dollar industry as healthcare sector and governments around the world increase their research spending.

The report analyzes the prevalent opportunities for the markets growth and those that companies should capitalize in the near future to strengthen their position in the market. It presents insights into the growth drivers and lists down the major restraints. Additionally, the report gauges the effect of Porters five forces on the overall stem cell assay market.

Global Stem Cell Assay Market: Key Market Segments

For the purpose of the study, the report segments the global stem cell assay market based on various parameters. For instance, in terms of assay type, the market can be segmented into isolation and purification, viability, cell identification, differentiation, proliferation, apoptosis, and function. By kit, the market can be bifurcated into human embryonic stem cell kits and adult stem cell kits. Based on instruments, flow cytometer, cell imaging systems, automated cell counter, and micro electrode arrays could be the key market segments.

In terms of application, the market can be segmented into drug discovery and development, clinical research, and regenerative medicine and therapy. The growth witnessed across the aforementioned application segments will be influenced by the increasing incidence of chronic ailments which will translate into the rising demand for regenerative medicines. Finally, based on end users, research institutes and industry research constitute the key market segments.

The report includes a detailed assessment of the various factors influencing the markets expansion across its key segments. The ones holding the most lucrative prospects are analyzed, and the factors restraining its trajectory across key segments are also discussed at length.

Global Stem Cell Assay Market: Regional Analysis

Regionally, the market is expected to witness heightened demand in the developed countries across Europe and North America. The increasing incidence of chronic ailments and the subsequently expanding patient population are the chief drivers of the stem cell assay market in North America. Besides this, the market is also expected to witness lucrative opportunities in Asia Pacific and Rest of the World.

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Global Stem Cell Assay Market: Vendor Landscape

A major inclusion in the report is the detailed assessment of the markets vendor landscape. For the purpose of the study the report therefore profiles some of the leading players having influence on the overall market dynamics. It also conducts SWOT analysis to study the strengths and weaknesses of the companies profiled and identify threats and opportunities that these enterprises are forecast to witness over the course of the reports forecast period.

Some of the most prominent enterprises operating in the global stem cell assay market are Bio-Rad Laboratories, Inc (U.S.), Thermo Fisher Scientific Inc. (U.S.), GE Healthcare (U.K.), Hemogenix Inc. (U.S.), Promega Corporation (U.S.), Bio-Techne Corporation (U.S.), Merck KGaA (Germany), STEMCELL Technologies Inc. (CA), Cell Biolabs, Inc. (U.S.), and Cellular Dynamics International, Inc. (U.S.).

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TMR Research is a premier provider of customized market research and consulting services to business entities keen on succeeding in todays supercharged economic climate. Armed with an experienced, dedicated, and dynamic team of analysts, we are redefining the way our clients conduct business by providing them with authoritative and trusted research studies in tune with the latest methodologies and market trends.

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Companies In The Global G-CSF (Granulocyte Colony Stimulating Factors) Market Are Focusing On Mergers And Acquisitions And Strategic Partnerships To…

By daniellenierenberg

LONDON, Jan. 14, 2021 (GLOBE NEWSWIRE) -- New year, new updates! Our reports have been revised for market size, forecasts, and strategies to take on 2021 after the COVID-19 impact: https://www.thebusinessresearchcompany.com/global-market-reports

As per The Business Research Companys research on the global granulocyte colony stimulating factors market, the focus areas for many companies in the G-CSF market has shifted to increasing mergers and acquisitions to acquire more production capabilities. Large prime manufactures are forming joint ventures or buying small or midsized companies to acquire new capabilities or gain access to new markets.

For instance, in June 2019, Pfizer Inc., a US-based pharmaceutical corporation, acquired Array BioPharma Inc. for $48 per share in cash, for a total enterprise value of approximately $11.4 billion. This acquisition strengthens Pfizers innovative biopharmaceutical business and is expected to accelerate its growth trajectory, particularly in the long term. Array BioPharma, a US-based company, is focused on the discovery, development and commercialization of targeted small molecule drugs to treat patients afflicted with cancer.

The G-CSF (Granulocyte Colony Stimulating Factors) market consists of sales of G-CSF drugs and related services. G-CSF-based drugs stimulate the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils through signal transduction pathways.

Granulocyte colony-stimulating factor based drugs are used to treat several pathophysiological conditions such as neutropenia (febrile neutropenia), acute radiation syndrome, auto-immune diseases and used during stem cell transplantation.

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The Business Research Companys report titled G-CSF (Granulocyte Colony Stimulating Factors) Global Market Report 2020-30: COVID-19 Growth And Change covers major G-CSF companies, Granulocyte Colony Stimulating Factorsmarket share by company, G-CSF manufacturers, G-CSF market size, and Granulocyte Colony Stimulating Factors market forecasts.

The G-CSF market is concentrated, with a small number of large players dominating the market. The top eight competitors in the market made up to 89.1% of the total market. The market is highly competitive. Companies in the market face completion for new product developments and technological advances. Major players in the market includes, Amgen Inc., Coherus Biosciences Inc., Sandoz (Novartis), Biocon/Mylan, Teva Pharmaceutcals Inc., Chugai Pharma Inc., Intalfarmaco Group, and Pfizer.

Companies in the Granolocyte Colony Stimulating Factors market are increasing their product innovation through strategic collaborations. To sustain in the increasingly competitive market, companies are developing innovative products as well as sharing skills and expertise with other companies. While companies have long collaborated with each other as well as with academic and research institutions in this market by way of partnerships, in or out-licensing deals, this trend has been increasing over recent years.

For instance, in September 2020, Humanigen, a clinical stage biopharmaceutical company collaborated with Lonza and Catalent to expand manufacturing of COVID-19 therapeutic candidate Lenzilumab. Lenzilumab is the patented Humaneered anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody with the potential to prevent and treat cytokine storm, which is believed to cause the acute respiratory distress syndrome in severe COVID-19 cases.

G-CSF (Granulocyte Colony Stimulating Factors) Market Global Report 2020-30: COVID-19 Growth And Change is one of a series of new reports from The Business Research Company that provide G-CSF market overviews, analyze and forecast Granulocyte Colony Stimulating Factors market size and growth for the whole market, G-CSF market segments and G-CSF market geographies, trends, market drivers, market restraints, G-CSF (Granulocyte Colony Stimulating Factors) market leading competitors revenues, profiles and market shares in over 1,000 industry reports, covering over 2,500 market segments and 60 geographies. The report also gives in-depth analysis of the impact of COVID-19 on the market.

The reports draw on 150,000 datasets, extensive secondary research, and exclusive insights from interviews with industry leaders. A highly experienced and expert team of analysts and modelers provides market analysis and forecasts. The reports identify top countries and segments for opportunities and strategies based on market trends and leading competitors approaches.

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Companies In The Global G-CSF (Granulocyte Colony Stimulating Factors) Market Are Focusing On Mergers And Acquisitions And Strategic Partnerships To...

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Magenta Therapeutics Highlights Recent Progress and Expected Timing of 2021 Milestones, Including Fo – PharmiWeb.com

By daniellenierenberg

-- MGTA-145: Three Phase 2 clinical trials ongoing or planned to evaluate MGTA-145, a biologic used in combination with plerixafor to mobilize stem cells; the first clinical trial in patients with multiple myeloma (initial data expected in mid-2021); the first clinical trial with matched donors and patients with acute myeloid leukemia (AML), acute lymphocytic lymphoma (ALL) and myelodysplastic syndromes (MDS) (data expected in the second half of 2021); and the first clinical trial in patients with sickle cell disease (trial initiation expected in the second half of 2021)

-- MGTA-117: Completing GLP toxicology and GMP manufacturing of targeted conditioning antibody-drug conjugate, MGTA-117; plans to initiate clinical trial in acute myeloid leukemia and myelodysplastic syndromes in mid-2021

-- Five abstracts from across Magentas pipeline, including four oral presentations, will be presented at the Transplantation and Cellular Therapy (TCT) Annual Meeting, to be held virtually February 8-12, 2021

-- Magenta also has announced the appointment of experienced biotech executive Alison Lawton to its Board of Directors --

-- Ended 2020 with cash reserves of approximately $145 million that are expected to fund the current operating plan into 2023 --

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of immune and blood systems reset via stem cell transplant to more patients, today highlighted progress across its stem cell mobilization and collection and targeted conditioning programs, and set expectations for 2021. These updates will be discussed during a webcast presentation at the 39th Annual J.P. Morgan Healthcare Conference on Thursday, January 14 at 7:50 a.m. PST / 10:50 a.m. EST.

Im exceptionally proud of the entire Magenta team who continued to adapt and execute across our portfolio, despite the disruptions that characterized 2020. This past year, we continued to drive our vision to bring immune and blood systems reset to more patients. We announced four pipeline-expanding partnerships, presented clinical and pre-clinical data across our pipeline and secured the capital that we expect can fund our operations into 2023. We continue to advance four ongoing and planned clinical trials that we believe can advance our portfolio in 2021 and, for MGTA-145 specifically, can provide proof-of-concept for stem cell mobilization across multiple diseases and the first clinical data for MGTA-117 targeted conditioning, said Jason Gardner, D. Phil., President and Chief Executive Officer, Magenta. I am also delighted to welcome Alison Lawtons return to Magentas Board of Directors. Alison brings extensive experience and leadership in both regulatory and business arenas, essential as the Magenta portfolio advances. We look forward to building on the momentum generated in 2020 as we relentlessly focus on execution.

Stem Cell Mobilization and Collection

MGTA-145: Three Phase 2 Clinical Trials Ongoing or Planned

Autologous Stem Cell Transplant of Multiple Myeloma Patients. Previously announced ongoing enrollment continues for the Phase 2 investigator-initiated clinical trial of MGTA-145, used in combination with plerixafor, to mobilize and collect stem cells for autologous stem cell transplantation in multiple myeloma patients at Stanford University. Magenta expects that this trial will provide data on stem cell mobilization and collection, durability of engraftment in transplanted patients and disease outcomes, including progression-free survival. Initial data from the study are expected in mid-2021.

Allogeneic Donor Stem Cell Mobilization and Collection for Stem Cell Transplant in AML, ALL and MDS Patients. Through a collaboration with the National Marrow Donor Program/Be The Match, Magenta plans to initiate, within the next several weeks, a Phase 2 clinical trial using MGTA-145 to mobilize and collect stem cells from allogeneic donors for transplant in patients with AML, ALL and MDS. This clinical trial will evaluate stem cell mobilization, collection, cell quality, engraftment and disease outcomes, including Graft-versus-Host Disease (GvHD), which is of particular importance in the allogeneic transplant setting. Initial data from this clinical trial are expected in the second half of 2021.

Sickle Cell Disease Stem Cell Mobilization and Collection; Cell Characterization; Pre-Clinical Gene Modification Model. In collaboration with bluebird bio, Magenta plans to initiate a Phase 2 clinical trial in the second half of 2021 to evaluate MGTA-145, in combination with plerixafor, for the mobilization and collection of stem cells in adults and adolescents with sickle cell disease (SCD). Each party will characterize the cells and Magenta plans to gene-correct the cells and transplant them into established pre-clinical disease models to evaluate engraftment. Data from this clinical trial could provide proof-of-concept for MGTA-145, in combination with plerixafor, as the preferred mobilization regimen for patients with SCD and, more broadly, across all gene therapy applications where safe, reliable and rapid mobilization of quality stem cells for gene-modification and transplant are necessary components.

About MGTA-145

Magenta is developing MGTA-145 in combination with plerixafor to harness complementary mechanisms to mobilize hematopoietic stem cells (HSCs) for collection and transplantation. This combination has the potential to be the preferred mobilization regimen for safe, rapid and reliable mobilization and collection of HSCs and could improve outcomes in autologous and allogeneic stem cell transplantation.

Targeted Conditioning

MGTA-117: Plans to Initiate Phase 1 Clinical Trial in mid-2021; Initial Safety and Pharmacokinetics (PK) data to be assessed in the fourth quarter of 2021

AML and MDS. Magenta is completing its IND-enabling GLP toxicology studies and GMP manufacturing process for MGTA-117, the first antibody-drug conjugate (ADC) candidate from the companys research platform for targeted conditioning of patients prior to receiving a stem cell transplant for blood cancers or gene therapy drug products. Later this month, Magenta expects to complete its initial discussions with the U.S. Food and Drug Administration regarding the design of the first-in-human clinical trial. Magenta expects to file an Investigational New Drug (IND) application and, upon approval, plans to initiate a Phase 1 clinical trial in mid-2021 to assess the safety and PK in the first cohort of patients in the fourth quarter of 2021.

About MGTA-117

MGTA-117, Magentas most advanced conditioning program, is a CD117-targeted antibody engineered for the transplant setting and conjugated to amanitin, a payload in-licensed from Heidelberg Pharma. MGTA-117 is designed to precisely deplete only hematopoietic stem and progenitor cells to clear space in the bone marrow prior to transplant, which supports long-term engraftment and disease outcomes in patients. MGTA-117 has shown high selectivity, potent efficacy, wide safety margins and broad tolerability in non-human primate models.

Cash Guidance

With focused allocation of resources on the Companys clinical trials and advancement of its research platform, the Company now believes its cash position will fund its operations into the first quarter of 2023.

Alison Lawton Background

Ms. Lawton is an executive leader with more than 30 years of experience in biopharma. She served as President and Chief Executive Officer of Kaleido Biosciences, Inc. (Nasdaq: KLDO) from August 2018 to June 2020, and served as President and Chief Operating Officer from December 2017 to August 2018. Prior to joining Kaleido Biosciences, Inc., Ms. Lawton served as Chief Operating Officer at Aura Biosciences, Inc., an oncology therapeutics company, from January 2015 until December 2017, and, prior to joining Aura, served as a consultant to Aura from March 2014 to December 2014. From January 2013 to January 2014, Ms. Lawton served as Chief Operating Officer at OvaScience Inc., a life sciences company. From 2014 to 2017, Ms. Lawton served as a biotech consultant for various companies, including as Chief Operating Officer consultant at X4 Pharmaceuticals. Prior to that, Ms. Lawton spent more than 20 years in various positions of increasing responsibility including Senior VP and General Manager of Biosurgery and prior, Senior VP of Market Access at Genzyme Corporation, a global biopharmaceutical company, and subsequently at Sanofi S.A., also a global biopharmaceutical company, following the acquisition of Genzyme by Sanofi in 2011. Additionally, Ms. Lawton previously served two terms as the industry representative on the U.S. Food & Drug Administrations Cell & Gene Therapy Advisory Committee and as Chairman of the Board of the Regulatory Affairs Professional Society. Ms. Lawton currently serves on the boards of directors of ProQR Therapeutics N.V., X4 Pharmaceuticals Inc. and Aeglea Biotherapeutics Inc. Ms. Lawton previously served on the boards of directors of Magenta Therapeutics, Kaleido Biosciences Inc., Verastem, Inc., CoLucid Pharmaceuticals, Inc. prior to its acquisition by Eli Lilly and Cubist Pharmaceuticals, Inc. prior to its acquisition by Merck & Co. Ms. Lawton holds a B.Sc. in pharmacology from Kings College, University of London.

Upcoming Presentations at the 2021 Transplantation and Cellular Therapy (TCT) Annual Meeting

Title: MGTA-145 / Plerixafor-Mediated HSC Mobilization and Intravenous HDAd5/35++ Vector Injection into Mice Allows for Efficient In Vivo HSC Transduction and Stable Gene Marking in Peripheral Blood Cells (Oral Abstract, #16)Presenting Author: Chang Li, Ph.D., Division of Medical Genetics, Department of Medicine, University of WashingtonDate and Time of Oral Presentation: Monday, February 8, 2021, 2:30 PM CST

Title: MGTA-145, In Combination with Plerixafor in a Phase 1 Clinical Study, Mobilizes Large Numbers of Hematopoietic Stem Cells and a Graft with Potent Immunosuppressive Properties for Autologous and Allogeneic Transplant (Oral Abstract, #35)Presenting Author: Kevin Goncalves, Ph.D., Magenta TherapeuticsDate and Time of Oral Presentation: Tuesday, February 9, 2021, 3:00 PM CST

Title: MGTA-456, A CD34 Expanded Cord Blood Product, Permits Selection of Better HLA Matched Units and Results in Rapid Hematopoietic Recovery, Uniform Engraftment and Reduced Graft-Versus-Host Disease in Adults with High-Risk Hematologic Malignancies (Oral Abstract, #31)Presenting Author: Heather Stefanski, M.D., Ph.D., Assistant Professor, Department of Pediatrics, University of MinnesotaDate and Time of Oral Presentation: Tuesday, February 9, 2021, 3:00 PM CST

Title: A Single Dose of a Novel Anti-Human CD117-Amanitin Antibody Drug Conjugate (ADC) Engineered for a Short Half-life Provides Dual Conditioning and Anti-Leukemia Activity and Extends Survival Compared to Standard of Care in Multiple Pre-clinical Models of Acute Myeloid Leukemia (AML) (Oral Abstract, #53)Presenting Author: Leanne Lanieri, M.S., Magenta TherapeuticsDate and Time of Oral Presentation: Wednesday, February 10, 2021, 3:00 PM CST

Title: Targeted CD45 Antibody Drug Conjugate Enables Full Mismatch Allogeneic Hematopoietic Stem Cell Transplantation in a Murine HSCT Model as a Single Agent (AML) (Poster #242)Lead Author: Sharon Hyzy, M.S., Magenta Therapeutics

About Magenta Therapeutics

Magenta Therapeutics is a clinical-stage biotechnology company developing medicines to bring the curative power of immune system reset through stem cell transplant to more patients with blood cancer, genetic diseases and autoimmune diseases. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise, a unique business model and broad networks in the stem cell transplant world to revolutionize immune reset for more patients.

Magenta is based in Cambridge, Mass. For more information, please visit http://www.magentatx.com.

Follow Magenta on Twitter: @magentatx.

Forward-Looking Statement

This press release may contain forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws, including express or implied statements regarding Magentas future expectations, plans and prospects, including, without limitation, statements regarding expectations and plans for presenting clinical data, projections regarding our long-term growth, cash, cash equivalents and marketable securities, the anticipated timing of our clinical trials and regulatory filings, the development of our product candidates and advancement of our clinical programs, the timing, progress and success of our collaborations, as well as other statements containing words such as may, will, could, should, expects, intends, plans, anticipates, believes, estimates, predicts, projects, seeks, endeavor, potential, continue or the negative of such words or other similar expressions that can be used to identify forward-looking statements. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation: uncertainties inherent in clinical studies and in the availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial will be predictive of the final results of the trial; whether results from pre-clinical studies or earlier clinical studies will be predictive of the results of future trials; the expected timing of submissions for regulatory approval or review by governmental authorities; regulatory approvals to conduct trials or to market products; whether Magenta's cash resources will be sufficient to fund Magenta's foreseeable and unforeseeable operating expenses and capital expenditure requirements; risks, assumptions and uncertainties regarding the impact of the continuing COVID-19 pandemic on Magentas business, operations, strategy, goals and anticipated timelines, Magentas ongoing and planned pre-clinical activities, Magentas ability to initiate, enroll, conduct or complete ongoing and planned clinical trials, Magentas timelines for regulatory submissions and Magentas financial position; and other risks concerning Magenta's programs and operations set forth under the caption Risk Factors in Magentas Annual Report on Form 10-K filed on March 3, 2020, as updated by Magentas most recent Quarterly Report on Form 10-Q and its other filings with the Securities and Exchange Commission. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although Magenta believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, except as required by law, neither Magenta nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Magenta Therapeutics:Lyndsey Scull, Director, Corporate Communications, Magenta Therapeutics202-213-7086lscull@magentatx.com

Investor inquiries:Jill Bertotti, W2O Group714-225-6726jbertotti@w2ogroup.com

Media inquiries:Dan Budwick1ABdan@1abmedia.com

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Cate Dyer of StemExpress is Named Businesswoman of the Year! – PRNewswire

By daniellenierenberg

SACRAMENTO, Calif., Jan. 12, 2021 /PRNewswire/ --The Sacramento Metropolitan Chamber of Commerce announced it will name Cate Dyer, CEO of StemExpress, the "Businesswoman of the Year" at their 126th Annual Business Awards. Since 1895, Metro Chamber has recognized Sacramento's most esteemed players in the business community. The 2021 Annual Dinner and Business Awards will be held virtually for the first time, and Ms. Dyer will receive this extraordinary honor on February 5th, 2021.

Ms. Dyer founded StemExpress in 2010 to accelerate the cure and prevention of significant medical conditions at life-changing speed. StemExpress supports medical research, clinical trials, commercialization of disease specific treatment, cell and gene therapies, precision and regenerative medicine, as well as researchers and clinicians from all around the world who are developing new treatments and cures. StemExpress has a network of healthcare partnerships that includes over 50 hospitals in Europe as well as three (3) US healthcare systems that encompasses 31 hospitals, 35 outpatient facilities and 20 individual practices. StemExpress is currently the nation's leading biospecimen provider of human primary cells, stem cells, human bone marrow, cord blood, peripheral blood, maternal blood, and disease-state products for academic, biotechnological, diagnostic, pharmaceutical and contract research organizations. StemExpress is registered with the U.S. Food and Drug Administration (FDA) and has seven (7) independently owned and operated brick-and mortar cellular clinics across the United States to collect blood, cells and tissue from patients and donors. These clinics include state-of-the-art cell manufacturing laboratories for clinical and research purposes, and CLIA certified/high-complexity diagnostics.

Since inception, StemExpress has been committed to transformative, positive impacts on the community. In line with this commitment, StemExpress immediately recognized the unparalleled challenges the COVID-19 virus presented to its communities, healthcare entities, local businesses, and the economy at large. In a matter of weeks, the company built out a seamless, end-to-end COVID-19 testing solution, all while continuing to grow its core cellular business. This end-to-end solution includes on-line patient registration, scheduling, specimen collection, pop-up site management, and laboratory testing using gold-standard PCR testing at high-volume capacity with rapid turn-around times. StemExpress directly and proudly supports frontline workers, inner city communities, hospitals, skilled nursing facilities, school districts, correctional facilities, utility companies, major league sports, tribal territories and territorial governments, among others. Through public health partnerships, StemExpress has also provided free testing services to vulnerable members of the community, including the uninsured and other under-represented populations.

The 2021 Annual Business Awards will pay tribute to Cate Dyer's extraordinary effort to support Sacramento's communities, businesses, and the heroes who keep our economy moving.

Contact: [emailprotected]

SOURCE StemExpress

https://www.stemexpress.com

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Errant Gene Therapeutics, LLC (EGT) Pushing Clinical Trial of Potentially Curative Treatment for Beta-Thalassemia and Eventually Sickle Cell Disease -…

By daniellenierenberg

TAMPA, Fla.--(BUSINESS WIRE)--The technology, developed by scientists at Memorial Sloan Kettering Cancer Center ("MSKCC"), headed by Dr. Michel Sadelain and Errant Gene Therapeutics, is a one-time treatment that inserts an encoded gene into a patient's own bone marrow stem cells restoring the production of normal hemoglobin. This technology is known as Thalagen.

In June of 2020, an abstract was released to the European Hematology Association (EHA) noting the results of patients treated in a clinical trial at MSK with the EGT vector. The abstract is based on patients treated with the 2009 EGT-produced vector in the MSK Clinical Trial. The EHA abstract, submitted by Simona Raso, reports that 2 out of 3 Thalassemia patients treated with EGTs vector have sustained dramatic reduction in blood transfusions after 8 and 5 years, respectively. These 3 patients are the only Thalassemic patients treated with Lentiglobin in the US for whom there is an 8-year follow-up. The abstract is publicly available on the European Hematology Associations website at the following address:

https://library.ehaweb.org/eha/2020/eha25th/293982/simona.raso.gene.therapy.with.the.lentiviral.vector.tns9.3.55.produces.html?f=menu%3D14%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Aspeaker%3D731017.

The reductions in transfusions for the patients reported in the EHA abstract means a marked reduction in risk and damage created by the chronic transfusions, transferred diseases and iron build-up. One of the patients with significant transfusion deduction used the EGT-produced vector with a mild chemotherapeutic prep-regimen. The abstract does not report any clonal dominance. EGT is the only company with experience in development of a non-myeloablative potential treatment for Thalassemia patients.

EGT produced the worlds first commercial batch of gene therapy vector in 2009. The EGT vector uses the wild-type beta globin gene, the most natural form of the gene.

EGT Founder, Patrick Girondi noted, After some delay, we are happy to be moving forward once again, and the EHA abstract is incredible news for patients. Today, with modern production, enhancers, improved filtration and other prep regimen drugs, we believe that the vector EGT will produce in 2021, honed by 12 years of advancement in the field and using modern transduction enhancers will cure Thalassemia patients and that EGT will make quick headway towards curing Sickle Cell patients using the same therapy.

EGT, a gene therapy pioneers goal is to make medicines which are safe and accessible to patients. EGT believes the EGT vector to be more natural and therefore safer. Additionally, the cost of the treatment is drastically lower than that of competing products. EGT will work with regulatory agencies to continue the trial, formerly sponsored by Memorial Sloan Kettering Cancer Center NCT01639690.

Ronald Capano of Cooleys Anemia International says, This clinical trial means so much to so many and represents the work and dedication of our organization and that of the family and friends of all Thalassemia and Sickle Cell anemia patients, particularly those with compromised organs.

About Errant Gene Therapeutics, LLC

Errant Gene Therapeutics (also known as EGT) is a privately held biopharmaceutical company established in 2003 headquartered in Tampa, Florida. In addition to its ongoing support of gene therapy for beta-thalassemia and Sickle Cell anemia, EGT is a pioneer in the emerging field of epigenetics, and its patented portfolio of small molecule histone deacetylase inhibitors, which change the way cells express their genetic material. EGTs lead compound, CG-1521, targets inflammatory breast cancer and hormone refractory prostate cancer. CG-1521 results have been published in scientific venues.

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Errant Gene Therapeutics, LLC ("EGT") Pushing Clinical Trial of Potentially Curative Treatment for Beta-Thalassemia and Eventually Sickle…

By daniellenierenberg

The technology, developed by scientists at Memorial Sloan Kettering Cancer Center ("MSKCC"), headed by Dr. Michel Sadelain and Errant Gene Therapeutics, is a one-time treatment that inserts an encoded gene into a patient's own bone marrow stem cells restoring the production of normal hemoglobin. This technology is known as Thalagen.

In June of 2020, an abstract was released to the European Hematology Association (EHA) noting the results of patients treated in a clinical trial at MSK with the EGT vector. The abstract is based on patients treated with the 2009 EGT-produced vector in the MSK Clinical Trial. The EHA abstract, submitted by Simona Raso, reports that 2 out of 3 Thalassemia patients treated with EGTs vector have sustained dramatic reduction in blood transfusions after 8 and 5 years, respectively. These 3 patients are the only Thalassemic patients treated with Lentiglobin in the US for whom there is an 8-year follow-up. The abstract is publicly available on the European Hematology Associations website at the following address:

https://library.ehaweb.org/eha/2020/eha25th/293982/simona.raso.gene.therapy.with.the.lentiviral.vector.tns9.3.55.produces.html?f=menu%3D14%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Aspeaker%3D731017.

The reductions in transfusions for the patients reported in the EHA abstract means a marked reduction in risk and damage created by the chronic transfusions, transferred diseases and iron build-up. One of the patients with significant transfusion deduction used the EGT-produced vector with a mild chemotherapeutic prep-regimen. The abstract does not report any clonal dominance. EGT is the only company with experience in development of a non-myeloablative potential treatment for Thalassemia patients.

EGT produced the worlds first commercial batch of gene therapy vector in 2009. The EGT vector uses the wild-type beta globin gene, the most natural form of the gene.

EGT Founder, Patrick Girondi noted, "After some delay, we are happy to be moving forward once again, and the EHA abstract is incredible news for patients. Today, with modern production, enhancers, improved filtration and other prep regimen drugs, we believe that the vector EGT will produce in 2021, honed by 12 years of advancement in the field and using modern transduction enhancers will cure Thalassemia patients and that EGT will make quick headway towards curing Sickle Cell patients using the same therapy."

Story continues

EGT, a gene therapy pioneers goal is to make medicines which are safe and accessible to patients. EGT believes the EGT vector to be more natural and therefore safer. Additionally, the cost of the treatment is drastically lower than that of competing products. EGT will work with regulatory agencies to continue the trial, formerly sponsored by Memorial Sloan Kettering Cancer Center NCT01639690.

Ronald Capano of Cooleys Anemia International says, "This clinical trial means so much to so many and represents the work and dedication of our organization and that of the family and friends of all Thalassemia and Sickle Cell anemia patients, particularly those with compromised organs."

About Errant Gene Therapeutics, LLC

Errant Gene Therapeutics (also known as EGT) is a privately held biopharmaceutical company established in 2003 headquartered in Tampa, Florida. In addition to its ongoing support of gene therapy for beta-thalassemia and Sickle Cell anemia, EGT is a pioneer in the emerging field of epigenetics, and its patented portfolio of small molecule histone deacetylase inhibitors, which change the way cells express their genetic material. EGTs lead compound, CG-1521, targets inflammatory breast cancer and hormone refractory prostate cancer. CG-1521 results have been published in scientific venues.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210111005273/en/

Contacts

Patrick Girondi, Founderpgirondi@errantgene.com (312) 441-1800 Office(312) 498-0025 Cell

Jason Feldman, BDOjfeldman@errantgene.com (312) 441-1800 x11

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Information and choices for women and couples at risk of having a baby with sickle cell disease – GOV.UK

By daniellenierenberg

Public Health England (PHE) created this information on behalf of the NHS. In this information, the word we refers to the NHS service that provides screening.

You should read this information if the result of your antenatal screening test for sickle cell and thalassaemia (SCT) shows you are at risk of having a baby with sickle cell disease.

This is because your blood test showed that:

This information will help you and your health professional talk through the next stages of your care during this pregnancy. It should support, but not replace, any discussions you have.

This information explains:

Sickle cell disease is the name for a group of conditions inherited from biological parents that affect the haemoglobin in red blood cells. The most serious type is called sickle cell anaemia.

In the UK, sickle cell disease is most common in people with an African or Caribbean family background, but it is also seen in people with family origins from other parts of the world.

People with sickle cell disease have red blood cells that can become misshapen, which:

Sickle cell disease is a serious lifelong condition, but long-term treatment can help manage many of the symptoms. People with sickle cell disease can lead long, active and fulfilling lives if they manage their condition well and have the right care and support.

The main symptoms of sickle cell disease are:

Other symptoms can include delayed growth, strokes and lung problems.

People with sickle cell disease need specialist care throughout their lives. Daily antibiotics and regular vaccinations can reduce the risk of infections. Blood transfusions can also be given to treat serious cases of anaemia. Some children with sickle cell disease benefit from taking a medicine called hydroxycarbamide which helps prevent many complications.

People with sickle cell disease can do a number of things to manage pain, avoid infections and stay as healthy as possible. Your healthcare professional can give you more advice about living with sickle cell disease.

The only cure for sickle cell disease is a bone marrow (or stem cell) transplant, which replaces damaged blood cells with healthy ones. This is a complicated procedure which is only suitable for people with serious complications from the disease who have a matching donor.

Sickle cell disease is inherited from genes passed on by both biological parents. It is not a result of anything you have or have not done.

If both biological parents are carriers of the haemoglobin gene, known as haemoglobin S, their baby can inherit the haemoglobin S gene from both of them. This is the most common and most serious type of sickle cell disease.

Babies can inherit other types of sickle cell disease if one parent carries the sickle cell gene (haemoglobin S) and the other parent has another haemoglobin gene such as beta thalassaemia or haemoglobin C. Your health professional can discuss this with you, so that you understand exactly what condition your baby could inherit, and how serious it could be.

If you and your childs biological father are both carriers then there is a 1 in 4 (25%) chance your child will inherit sickle cell disease. There is a 2 in 4 (50%) chance that your child will be a carrier, and a 1 in 4 (25%) chance your child will have normal haemoglobin. These chances are the same in every pregnancy when both parents are carriers.

The diagram below shows how genetic inheritance works. Both parents in this diagram are carriers. They are drawn in 2 colours to show they have one usual haemoglobin gene (green) and one unusual gene (blue).

There is a 1 in 4 chance of this baby inheriting the condition, a 2 in 4 chance of them being a carrier and a 1 in 4 chance they will not have the condition.

You can choose if you want a test to find out for sure if your unborn baby has inherited sickle cell disease or not. This is called prenatal diagnosis (PND). It is your decision to have this test or not.

All babies are offered the newborn blood spot test for sickle cell disease whether a PND has been carried out or not. The test is offered when the baby is 5 days old and results received before the baby is 28 days old.

You will be offered either a chorionic villus sampling (CVS) or amniocentesis diagnostic test.

CVS tests are usually done between 11 and 14 weeks of pregnancy but can be done later.

Amniocentesis tests are usually done between 15 and 20 weeks of pregnancy.

There are 3 possible results from a PND test. It can show that your baby:

In rare cases the screening laboratory cannot give a result. If this happens, you will be contacted and offered a repeat PND test.

If the result shows that your baby has normal haemoglobin or is a carrier, then your pregnancy care will continue as usual.

If a PND test shows your baby has inherited sickle cell disease, your healthcare professional will talk to you and offer support. You should also have the chance to talk to a specialist.

You may choose to:

If you decide to continue with the pregnancy the specialist team will:

If you decide to end your pregnancy the specialist team will give you information about what this involves and how you will be supported.

Only you know what is the best decision for your family.

Whatever decision you make, your healthcare professionals will support you.

If you and your partner are planning a pregnancy and are both carriers, there is a 1 in 4 (25%) chance your baby could inherit sickle cell disease. These chances are the same in each and every pregnancy that you have together.

You may discuss the following with your GP, midwife or specialist counsellor:

This can be performed after 11 weeks giving more time to consider your choices if the baby has sickle cell disease. You would need to see your GP or midwife as soon as you know you are pregnant.

PGD is a reproductive treatment used in in-vitro fertilisation (IVF) which involves checking the genes or chromosomes of your embryos for a specific genetic condition. It can help to avoid a pregnancy with a genetic condition for which a couple is at risk. You can ask to see a genetic counsellor to discuss this option.

This means either you or your partner would not be a biological parent of your baby. You can discuss this option with your healthcare professional.

For more information, see:

The NHS Screening Programmes use personal information from your NHS records to invite you for screening at the right time. Public Health England also uses your information to ensure you receive high quality care and to improve the screening programmes. Find out more about how your information is used and protected, and your options.

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MorphoSys and Incyte Announce Acceptance by Health Canada of the New Drug Submission for Tafasitamab – PharmiWeb.com

By daniellenierenberg

DGAP-News: MorphoSys AG / Key word(s): Miscellaneous12.01.2021 / 22:00 The issuer is solely responsible for the content of this announcement.

Media Release

MorphoSys and Incyte Announce Acceptance by Health Canada of the New Drug Submission for Tafasitamab

PLANEGG/MUNICH, Germany and MONTREAL, Canada - January 12, 2021 - MorphoSys AG (FSE: MOR; Prime Standard Segment; MDAX & TecDAX; NASDAQ:MOR) and Incyte (NASDAQ: INCY) today announced that Health Canada has accepted the New Drug Submission (NDS) for tafasitamab, an anti-CD19 antibody. The application seeks approval of tafasitamab in combination with lenalidomide, followed by tafasitamab monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade lymphoma, who are not eligible for, or refuse, autologous stem cell transplant (ASCT).

"With the acceptance of the NDS by Health Canada, review of the data can begin, an important step on the path to making tafasitamab available in Canada for use in combination with lenalidomide in eligible patients with relapsed or refractory DLBCL," said Jose Brisebois, Ph.D., Head of Medical Affairs, Incyte Biosciences Canada. "We intend to work closely with Health Canada as we seek to bring this innovative targeted therapeutic option to the clinical community and to appropriate patients for whom few treatment options exist."

"This important milestone moves tafasitamab in combination with lenalidomide into the regulatory review process in Canada, with the potential to significantly advance patient care in the treatment of relapsed or refractory DLBCL," said Nuwan Kurukulasuriya, Ph.D., Senior Vice President Global Medical Affairs, MorphoSys.

The NDS, submitted by Incyte, is based on data from the L-MIND study evaluating tafasitamab in combination with lenalidomide as a treatment for patients with relapsed or refractory DLBCL not eligible for autologous stem cell transplant, and is supported by the RE-MIND study, an observational retrospective study in relapsed or refractory DLBCL.

Incyte has exclusive commercialization rights for tafasitamab outside of the United States and, if approved, Incyte will hold the marketing authorization for tafasitamab in Canada. This NDS marks the second marketing application that Incyte Biosciences Canada has made to Health Canada since establishing operations in Canada in April 2020.

About Diffuse Large B-cell Lymphoma (DLBCL)DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide1, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about 40% of patients not responding to initial therapy or relapsing thereafter2, leading to a high medical need for new, effective therapies3, especially for patients who are not eligible for an autologous stem cell transplant in this setting.

About L-MINDThe L-MIND trial is a single arm, open-label, multicenter Phase 2 study (NCT02399085) investigating the combination of tafasitamab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have had at least one, but no more than three prior lines of therapy, including an anti-CD20 targeting therapy (e.g. rituximab), who are not eligible for high-dose chemotherapy or refuse subsequent autologous stem cell transplant. The study's primary endpoint is Overall Response Rate (ORR). Secondary outcome measures include Duration of Response (DoR), Progression-Free Survival (PFS) and Overall Survival (OS). In May 2019, the study reached its primary completion.

For more information about L-MIND, visit https://clinicaltrials.gov/ct2/show/NCT02399085

About RE-MINDRE-MIND, an observational retrospective study (NCT04150328), was designed to isolate the contribution of tafasitamab in combination with lenalidomide and to prove the combinatorial effect. The study compares real-world response data of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received lenalidomide monotherapy with the efficacy outcomes of the tafasitamab-lenalidomide combination, as investigated in MorphoSys' L-MIND trial. RE-MIND collected the efficacy data from 490 relapsed or refractory DLBCL patients in the U.S. and EU. Qualification criteria for matching patients of both studies were pre-specified. As a result, 76 eligible RE-MIND patients were identified and matched 1:1 to 76 of 80 L-MIND patients based on important baseline characteristics. Objective Response Rates (ORR) were validated based on this subset of 76 patients in RE-MIND and L-MIND, respectively. The primary endpoint of RE-MIND was met and shows a statistically significant superior best ORR of the tafasitamab-lenalidomide combination compared to lenalidomide monotherapy.

For more information about RE-MIND, visit https://clinicaltrials.gov/ct2/show/NCT04150328.

About TafasitamabTafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb(R) engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP). In January 2020, MorphoSys and Incyte entered into a collaboration and licensing agreement to further develop and commercialize tafasitamab globally. Following approval by the U.S. Food and Drug Administration in July 2020, tafasitamab is being co-commercialized by MorphoSys and Incyte in the United States. Incyte has exclusive commercialization rights outside the United States.

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in a number of ongoing combination trials.

XmAb(R) is a registered trademark of Xencor, Inc.

The safety and efficacy of tafasitamab is under review and the market authorization in Canada has not yet been obtained.

About MorphoSysMorphoSys (FSE & NASDAQ: MOR) is a commercial-stage biopharmaceutical company dedicated to the discovery, development and commercialization of innovative therapies for patients suffering from cancer and autoimmune diseases. Based on its leading expertise in antibody, protein and peptide technologies, MorphoSys, together with its partners, has developed and contributed to the development of more than 100 product candidates, of which 27 are currently in clinical development. In 2017, Tremfya(R), developed by Janssen Research & Development, LLC and marketed by Janssen Biotech, Inc., for the treatment of plaque psoriasis, became the first drug based on MorphoSys' antibody technology to receive regulatory approval. In July 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval of MorphoSys' proprietary product Monjuvi(R) (tafasitamab-cxix) in combination with lenalidomide in patients with a certain type of lymphoma. Headquartered near Munich, Germany, the MorphoSys group, including the fully owned U.S. subsidiary MorphoSys US Inc., has more than 600 employees. More information at http://www.morphosys.com or http://www.morphosys-us.com.

Monjuvi(R) is a registered trademark of MorphoSys AG.

Tremfya(R) is a registered trademark of Janssen Biotech, Inc.

About Incyte Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development and commercialization of proprietary therapeutics. For additional information on Incyte, please visit Incyte.com and follow @Incyte.

MorphoSys Forward-looking Statements This communication contains certain forward-looking statements concerning the MorphoSys group of companies, including the expectations regarding Monjuvi's ability to treat patients with relapsed or refractory diffuse large B-cell lymphoma, the further clinical development of tafasitamab-cxix, including ongoing confirmatory trials, additional interactions with regulatory authorities and expectations regarding future regulatory filings and possible additional approvals for tafasitamab-cxix as well as the commercial performance of Monjuvi. The words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "would," "could," "potential," "possible," "hope" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The forward-looking statements contained herein represent the judgment of MorphoSys as of the date of this release and involve known and unknown risks and uncertainties, which might cause the actual results, financial condition and liquidity, performance or achievements of MorphoSys, or industry results, to be materially different from any historic or future results, financial conditions and liquidity, performance or achievements expressed or implied by such forward-looking statements. In addition, even if MorphoSys' results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. Among the factors that may result in differences are MorphoSys' expectations regarding risks and uncertainties related to the impact of the COVID-19 pandemic to MorphoSys' business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products, the global collaboration and license agreement for tafasitamab, the further clinical development of tafasitamab, including ongoing confirmatory trials, and MorphoSys' ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials, additional interactions with regulatory authorities and expectations regarding future regulatory filings and possible additional approvals for tafasitamab-cxix as well as the commercial performance of Monjuvi, MorphoSys' reliance on collaborations with third parties, estimating the commercial potential of its development programs and other risks indicated in the risk factors included in MorphoSys' Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. MorphoSys expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements, unless specifically required by law or regulation.

Incyte Forward-looking Statements Except for the historical information set forth herein, the matters set forth in this press release, including statements regarding whether or when tafasitamab might be approved in Canada for the treatment of, and whether or when tafasitamab might provide a successful treatment option for, in combination with lenalidomide, certain patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and the L-MIND and RE-MIND clinical trial programs. These forward-looking statements are based on the Company's current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: unanticipated delays; further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials; determinations made by Canadian regulatory authorities or other regulatory authorities, including the U.S. FDA; the Company's dependence on its relationships with its collaboration partners; the efficacy or safety of the Company's products and the products of the Company's collaboration partners; the acceptance of the Company's products and the products of the Company's collaboration partners in the marketplace; market competition; sales, marketing, manufacturing and distribution requirements; greater than expected expenses; expenses relating to litigation or strategic activities; and other risks detailed from time to time in the Company's reports filed with the Securities and Exchange Commission, including its Form 10-Q for the quarter ending September 30, 2020. The Company disclaims any intent or obligation to update these forward-looking statements.

Contacts:

References1Sarkozy C, et al. Management of relapsed/refractory DLBCL. Best Practice Research & Clinical Haematology. 2018 31:209-16. doi.org/10.1016/j.beha.2018.07.014.2 Skrabek P, et al. Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma. Current Oncology. 2019 26(4): 253-265. doi.org/10.3747/co.26.5421.3 Skrabek P, et al. Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma. Current Oncology. 2019 26(4): 253-265. doi.org/10.3747/co.26.5421.

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MorphoSys and Incyte Announce Acceptance by Health Canada of the New Drug Submission for Tafasitamab - PharmiWeb.com

To Read More: MorphoSys and Incyte Announce Acceptance by Health Canada of the New Drug Submission for Tafasitamab – PharmiWeb.com
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Warm Up with Homemade Broths and Stocks – The Source Weekly

By daniellenierenberg

Abowl of hot soup or warm broth can take the chill out of a cold winter day. While grocery store shelves are usually stocked with an array of canned and boxed varieties, making a delicious broth for sipping or a stock as a base for other soups and recipes is something you can do while doing other things, such as working on your computer or doing the laundry. Once you get it going, you only have to check on it occasionally until it's done.

According to Food & Wine, the difference between stock and broth is minimal. A stock is to be made with bones in addition to a mirepoix, a mix of carrots, onions and celery. At its most basic, broth is simply any liquid that meat has been cooked in. A broth can also be made with just vegetables. While broth is something you sip, stock is typically used as a base in sauces and soups, providing body rather than flavor.

As author Sally Fallon Morell points out in her book, "Nourishing Broth: An Old-Fashioned Remedy for the Modern World," bone broth has rich dissolves of collagen, cartilage, bone and marrow which give the body the right stuff to rebuild and rejuvenatestuff such as vitamins, minerals, amino acids and healing sugars.

"Deep in the center of bones is marrow, a creamy substance valued by our ancestors for its life-giving, reproduction-enhancing, and brain-building fat and cholesterol. As the seed of blood and stem cells, it's prized as a sacred, energizing, and regenerative food in native cultures all over the world," Morell writes. Of course, most are aware of the benefits of eating plenty of plants in our diet, too.

Whether you're going for bones or carrots or both, the basic technique is the same. Simmer veggie scraps or bones in water for a long, slow time (in the case of straight-up vegetable broth, it can be finished in one hour or less).

Simple Vegetable BrothA swirl of your favorite oil1 onion, chopped2 stalks celery, chopped2 large carrots, choppedLeftover vegetable scraps you have on hand (onion skins, carrot ends, celery leaves, herbs, potato peels, greens, etc.)Several cloves of garlic, smashedFresh parsley/thymePinch of saltTwo bay leavesWater to cover

Saut chopped veggies in a bit of oil or water to soften. Add salt, herbs, bay leaves and water to cover. Bring to almost boiling, then turn heat down to simmer for 45-60 minutes, longer if desired. Strain. Cool.

Basic Bone Broth

Roast bones on baking sheet in hot oven (400 degrees) for 30 minutes. Place bones and vegetables in big pot. Cover with water. Bring to an easy roll then immediately turn heat down. Simmer uncovered, skimming scum as it rises. Cook for 24-72 hours. Turn off overnight, turn back on to simmer next morning. During last 10 minutes of cooking, toss in fresh parsley for added flavor. Let broth cool before straining. Store in fridge up to one week or freezer up to six months.

Pro Tips:

The number one goal for bone broth/stock is to get it gelatinous, meaning it sets up in a solid gel if you put it in the fridge. Bones, such as knucklebones and chicken/pig feet with lots of cartilage help make the broth gelatinous. Include meaty bones, such as short ribs, to add flavor.

Water should just cover the bones.

Never overheat the broth/stock. A roiling boil will break down collagen fibers that won't coagulate when cooled. So heat over medium heat only until the liquid starts to "roll," then turn the heat down until it barely simmers.

Simmer with the lid off to prevent boiling and allow the gradual reduction of the stock and concentration of gelatin.

To avoid cloudiness, skim the scum that rises to the top as the liquid starts to cook and occasionally throughout cooking.

To freeze stock, only fill the container full.

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Warm Up with Homemade Broths and Stocks - The Source Weekly

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Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine – Science Advances

By daniellenierenberg

Abstract

Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factorAB and 5-azacytidine into multipotent stem cells with stromal cell characteristics. We have now optimized culture conditions to reprogram human adipocytes into induced multipotent stem (iMS) cells and characterized their molecular and functional properties. Although the basal transcriptomes of adipocyte-derived iMS cells and adipose tissuederived mesenchymal stem cells were similar, there were changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to muscle, bone, cartilage, and blood vessels, with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibers without ectopic tissue formation. Together, human adipocytederived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth.

The goal of regenerative medicine is to restore function by reconstituting dysfunctional tissues. Most tissues have a reservoir of tissue-resident stem cells with restricted cell fates suited to the regeneration of the tissue in which they reside (14). The innate regenerative capacity of a tissue is broadly related to the basal rate of tissue turnover, the health of resident stem cells, and the hostility of the local environment. Bone marrow transplants and tissue grafts are frequently used in clinical practice but for most tissues, harvesting and expanding stem and progenitor cells are currently not a viable option (5, 6). Given these constraints, research efforts have been focused on converting terminally differentiated cells into pluripotent or lineage-restricted stem cells (7, 8). However, tissues are often a complex mix of diverse cell types that are derived from distinct stem cells. Therefore, multipotent stem cells may have advantages over tissue-specific stem cells. To be of use in regenerative medicine, these cells would need to respond appropriately to regional cues and participate in context-dependent tissue regeneration without forming ectopic tissues or teratomas. Mesenchymal stem cells (MSCs) were thought to have some of these characteristics (911), but despite numerous ongoing clinical trials, evidence for their direct contribution to new tissue formation in humans is sparse, either due to the lack of sufficient means to trace cell fate in hosts in vivo or failure of these cells to regenerate tissues (12, 13).

We previously reported a method by which primary terminally differentiated somatic cells could be converted into multipotent stem cells, which we termed as induced multipotent stem (iMS) cells (14). These cells were generated by transiently culturing primary mouse osteocytes in medium supplemented with azacitidine (AZA; 2 days) and platelet-derived growth factorAB (PDGF-AB; 8 days). Although the precise mechanisms by which these agents promoted cell conversion was unclear, the net effect was reduced DNA methylation at the OCT4 promoter and reexpression of pluripotency factors (OCT4, KLF4, SOX2, c-MYC, SSEA-1, and NANOG) in 2 to 4% of treated osteocytes. iMS cells resembled MSCs with comparable morphology, cell surface phenotype, colony-forming unit fibroblast (CFU-F), long-term growth, clonogenicity, and multilineage in vitro differentiation potential. iMS cells also contributed directly to in vivo tissue regeneration and did so in a context-dependent manner without forming teratomas. In proof-of-principle experiments, we also showed that primary mouse and human adipocytes could be converted into long-term repopulating CFU-Fs by this method using a suitably modified protocol (14).

AZA, one of the agents used in this protocol, is a cytidine nucleoside analog and a DNA hypomethylating agent that is routinely used in clinical practice for patients with higher-risk myelodysplastic syndrome (MDS) and for elderly patients with acute myeloid leukemia (AML) who are intolerant to intensive chemotherapy (15, 16). AZA is incorporated primarily into RNA, disrupting transcription and protein synthesis. However, 10 to 35% of drug is incorporated into DNA resulting in the entrapment and depletion of DNA methyltransferases and suppression of DNA methylation (17). Although the relationship between DNA hypomethylation and therapeutic efficacy in MDS/AML is unclear, AZA is known to induce an interferon response and apoptosis in proliferating cells (1820). PDGF-AB, the other critical reprogramming agent, is one of five PDGF isoforms (PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD), which bind to one of two PDGF receptors (PDGFR and PDGFR) (21). PDGF isoforms are potent mitogens for mesenchymal cells, and recombinant human (rh)PDGF-BB is used as an osteoinductive agent in the clinic (22). PDGF-AB binds preferentially to PDGFR and induces PDGFR- homodimers or PDGFR- heterodimers. These are activated by autophosphorylation to create docking sites for a variety of downstream signaling molecules (23). Although we have previously demonstrated induction of CFU-Fs from human adipocytes using PDGF-AB/AZA (14), the molecular changes, which underlie conversion, and the multilineage differentiation potential and in vivo regenerative capacity of the converted cells have not been determined.

Here, we report an optimized PDGF-AB/AZA treatment protocol that was used to convert primary human adipocytes, a tissue source that is easily accessible and requires minimal manipulation, from adult donors aged 27 to 66 years into iMS cells with long-term repopulating capacity and multilineage differentiation potential. We also report the molecular landscape of these human iMS cells along with that of MSCs derived from matched adipose tissues and the comparative in vivo regenerative and teratogenic potential of these cells in mouse xenograft models.

Primary mature human adipocytes were harvested from subcutaneous fat (Fig. 1A and table S1) and their purity confirmed by flow cytometry with specific attention to the absence of contaminating adipose-derived MSCs (AdMSCs) (fig. S1, A and B). As previously described (14), plastic adherent adipocytes were cultured in Alpha Minimum Essential Medium (MEM) containing rhPDGF-AB (200 ng/ml) and 20% autologous serum (AS) with and without 10 M AZA for 2 and 23 days, respectively (Fig. 1A). During daily observations, unilocular lipid globules were observed to fragment within adipocytes ~day 10 with progressive extrusion of fat into culture medium, coincident with changes in cell morphology (movie S1). Consistent with these observations, when fixed and stained with Oil Red O, adipocytes that were globular in shape at the start of culture resembled lipid laden stromal cells at day 12 and lipid-free stromal cells at day 25 (Fig. 1B).

(A) Generation and reprogramming of adipocytes. (B) Oil Red Ostained adipocytes (days 0, 12, and 25) during treatment with recombinant human platelet-derived growth factorAB (rhPDGF-AB) and AZA. (C) Flow cytometry plots of LipidTOX and PDGFR in adipocytes cultured as in (A). (D) CFU-F counts from treated and untreated adipocytes during conversion. (E) CFU-F counts from adipocytes treated (Rx) with indicated combinations of rhPDGF-AB, AZA, fetal calf serum (FCS), autologous serum (AS), or serum-free media (SFM). (F) CFU-F counts from adipocytes reprogrammed in the presence of 0, 1, or 10 M PDGFR/ inhibitor AG1296. (G) CFU-F counts per 400 reprogrammed adipocytes from three donor age groups (n = 3 for each) generated using indicated combinations of rhPDGF-AB and AZA. (H) Long-term growth of reprogrammed adipocytes from three donor age groups (n = 3 for each) generated using indicated combinations of rhPDGF-AB and AZA. (I) Long-term growth of iMS cells cultured in SFM or media supplemented with FCS, autologous, or allogeneic serum. Error bars indicate SD, n = 3; *P < 0.05, **P < 0.01, and ***P < 0.0001 calculated using either a Students t test (E and F) or a linear mixed model (H). Photo credit: Avani Yeola, UNSW Sydney.

To evaluate these changes in individual cells, we performed flow cytometry at multiple time points during treatment and probed for adipocyte (LipidTOX) (24) and stromal cell characteristics [PDGFR expression (25); Fig. 1C]. A subpopulation of adipocytes, when cultured in media supplemented with PDGF-AB/AZA and AS (Fig. 1C, top; treated), showed reduced LipidTOX staining intensity at day 10, with progressive reduction and complete absence in all cells by day 19. Adipocytes cultured in the absence of PDGF-AB/AZA retained LipidTOX staining, albeit with reduced intensity (Fig. 1C, bottom; untreated). Adipocytes expressed PDGFR [fig. S1C, (i) and (ii)] but not PDGFR (Fig. 1C) at day 0 but both the frequency and intensity of PDGFR staining increased from day 21. To record these changes in real time, we also continuously live-imaged treated adipocytes from days 15 to 25 and recorded the extrusion of fat globules, change in cell morphology from globular to stromal, and acquisition of cell motility and cell mitosis (movie S1 and fig. S1D). Intracellular fragmentation of fat globules was observed over time in untreated adipocytes (fig. S1E), consistent with variable LipidTOX staining intensity. CFU-F capacity was absent at day 10, present in day 15 cultures, and tripled by day 19 with no substantial increase at days 21, 23, and 25 (Fig. 1D). It is noteworthy that CFU-F potential was acquired before PDGFRA surface expression when adipocytes had started to display stromal cell morphology and had diminished fat content. There was also no CFU-F capacity in adipocytes cultured in MEM with fetal calf serum (FCS) or AS, unless supplemented with both PDGF-AB and AZA. CFU-F capacity was significantly higher with AS than with FCS and absent in serum-free media (SFM) (Fig. 1E and fig. S1F). As previously shown with reprogramming of murine osteocytes, there was dose-dependent inhibition of CFU-F capacity when AG1296, a potent nonselective PDGF receptor tyrosine kinase inhibitor (26), was added to the reprogramming media (Fig. 1F).

To evaluate the impact of patient age and concentrations of PDGF-AB and AZA on the efficiency of human adipocyte conversion, we harvested subcutaneous fat from donors aged 40 (n = 3), 41 to 60 (n = 3), and 61 (n = 3) years and subjected each to three different concentrations of PDGF-AB (100, 200, and 400 ng/ml) and three different concentrations of AZA (5, 10, and 20 M) (Fig. 1G). Although all combinations supported cell conversion in all donors across the three age groups, rhPDGF-AB (400 ng/ml) and 5 M AZA yielded the highest number of CFU-Fs (Fig. 1G). When these cultures were serially passaged in SFM (with no PDGF-AB/AZA supplementation, which was used for cell conversion only), adipocytes converted with reprogramming media containing rhPDGF-AB (400 ng/ml) and 5 M AZA were sustained the longest (Fig. 1H, fig. S2A, and table S2). The growth plateau that was observed even with these cultures [i.e., adipocytes converted with rhPDGF-AB (400 ng/ml) and 5 M AZA when expanded in SFM or FCS] was overcome when cells were expanded in either autologous or allogeneic human serum (Fig. 1I). The genetic stability of human iMS cells (RM0072 and RM0073) was also assessed using single-nucleotide polymorphism arrays and shown to have a normal copy number profile at a resolution of 250 kb (fig. S2B). Together, these data identify an optimized protocol for converting human primary adipocytes from donors across different age groups and show that these can be maintained long term in culture.

Given the stromal characteristics observed in human adipocytes treated with PDGF-AB/AZA (Fig. 1), we performed flow cytometry to evaluate their expression of MSC markers CD73, CD90, CD105, and STRO1 (13) and noted expression levels comparable to AdMSCs extracted from the same subcutaneous fat harvest (Fig. 2A). Primary untreated adipocytes (day 25 in culture) did not express any of these MSC markers (fig. S3A). The global transcriptomes of iMS cells and matched AdMSCs were distinct from untreated control adipocytes but were broadly related to each other [Fig. 2B, (i) and (ii)]. Ingenuity pathway analysis (IPA) using genes that were differentially expressed between AdMSCs versus adipocytes [3307 UP/4351 DOWN in AdMSCs versus adipocytes; false discovery rate (FDR) 0.05] and iMS versus adipocytes (3311 UP/4400 DOWN in iMS versus adipocytes; FDR 0.05) showed changes associated with gene expression, posttranslational modification, and cell survival pathways and organismal survival and systems development [Fig. 2B(iii)]. The number of differentially expressed genes between iMS cells and AdMSCs was limited (2 UP/26 DOWN in iMS versus AdMSCs; FDR 0.05) and too few for confident IPA annotation. All differentially expressed genes and IPA annotations are shown in table S3 (A to E, respectively).

(A) Flow cytometry for stromal markers on AdMSCs (green) and iMS cells (purple) from matched donors. Gray, unstained controls. (B) (i) Principal components analysis (PCA) plot of adipocyte, AdMSC, and iMS transcriptomes. (ii) Hierarchical clustering of differentially expressed genes (DEGs, FDR 0.05). (iii) Ingenuity pathway analysis (IPA) of DEG between AdMSCs/adipocytes (top) or iMS cells/adipocytes (bottom). The most enriched annotated biological functions are shown. (C) (i) Chromatin immunoprecipitation sequencing (ChIP-seq) profiles in AdMSCs and iMS cells from matched donors at a representative locus. Gray bar indicates differential enrichment. (ii) Volcano plots of H3K4me3, H3K27Ac, and H3K27me3 enrichment peaks significantly UP (red) or DOWN (blue) in iMS cells versus AdMSCs. (iii) IPA of corresponding genes. log2FC, log2 fold change. (D) (i) DNA methylation at a representative locus in AdMSCs and iMS cells from matched donors. (ii) Volcano plot of regions with significantly higher (red) or lower (blue) DNA methylation in iMS cells versus AdMSCs. (iii) IPA using genes corresponding to differentially methylated regions (DMRs). (E) OCT4, NANOG, and SOX2 expression in iPS, AdMSCs, and iMS cells. Percentage of cells expressing each protein is indicated. DAPI, 4,6-diamidino-2-phenylindole. (F) AdMSCs and iMS cells differentiated in vitro. Bar graphs quantify staining frequencies, error bars show SD, n = 3. ***P < 0.001 (Students t test). Photo credit: Avani Yeola, UNSW Sydney.

In the absence of significant basal differences in the transcriptomes of AdMSCs and iMS cells, and the use of a hypomethylating agent to induce adipocyte conversion into iMS cells, we examined global enrichment profiles of histone marks associated with transcriptionally active (H3K4me3 and H3K27Ac) and inactive (H3K27me3) chromatin. There were differences in enrichment of specific histone marks in matched AdMSCs versus iMS cells at gene promoters and distal regulatory regions [Fig. 2C(i) and fig. S3, B to D]. H3K4me3, H3K27ac, and H3K27me3 enrichments were significantly higher at 255, 107, and 549 regions and significantly lower at 222, 78, and 98 regions in iMS cells versus AdMSCs [Fig. 2C(ii) and table S4, A to C] and were assigned to 237, 84, and 350 and 191, 58, and 67 genes, respectively. IPA was performed using these gene lists to identify biological functions that may be primed in iMS cells relative to AdMSCs [Fig. 2C(iii) and table S4, D to F]. Among these biological functions, annotations for molecular and cellular function (cellular movement, development, growth, and proliferation) and systems development (general; embryonic and tissue development and specific; cardiovascular, skeletal and muscular, and hematological) featured strongly and overlapped across the different epigenetic marks.

We extended these analyses to also assess global CpG methylation in matched AdMSCs and iMS cells using reduced representation bisulfite sequencing [RRBS; (27)]. Again, there were loci with differentially methylated regions (DMRs) in iMS cells versus AdMSCs [Fig. 2D(i)] with increased methylation at 158 and reduced methylation at 397 regions among all regions assessed [Fig. 2D(ii) and table S4G]. IPA of genes associated with these DMRs showed a notable overlap in annotated biological functions [Fig. 2D(iii) and table S4H] with those associated with differential H3K4me3, H3K27Ac, and H3K27me3 enrichment [Fig. 2C(iii) and table S4, E to G]. Together, these data imply that although basal transcriptomic differences between iMS cells and AdMSCs were limited, there were notable differences in epigenetic profiles at cis-regulatory regions of genes that were associated with cellular growth and systems development.

We next compared iMS cells to adipocytes from which they were derived. Expression of genes associated with adipogenesis was depleted in iMS cells (fig. S4A and table S4I). The promoter regions of these genes in iMS cells had broadly retained an active histone mark (H3K4me3), but, in contrast with adipocytes, many had acquired an inactive mark (H3K27me3) (fig. S4B and table S4J). However, there were examples where iMS cells had lost active histone marks (H3K4me3 and H3K27ac) at gene promoters and potential regulatory regions and gained repressive H3K27me3 [e.g., ADIPOQ; fig. S4C(i)]. In contrast, stromal genes had acquired active histone marks and lost repressive H3K27me3 [e.g. EPH2A; fig. S4C(ii)]. It is noteworthy that promoter regions of genes associated with muscle and pericytes (table S4K) were enriched for active histone marks in iMS cells compared with adipocytes [fig. S4D, (i) and (ii)]. We also compared demethylated CpGs in iMS cells and adipocytes (fig. S4E). There were 7366 sites in 2971 genes that were hypomethylated in iMS cells, of which 236 showed increased expression and were enriched for genes associated with tissue development and cellular growth and proliferation (fig. S4E).

PDGF-AB/AZAtreated murine osteocytes (murine iMS cells), but not bone-derived MSCs, expressed pluripotency associated genes, which were detectable by immunohistochemistry in 1 to 4% of cells (14). To evaluate expression in reprogrammed human cells, PDGF-AB/AZAtreated human adipocytes and matched AdMSCs were stained for OCT4, NANOG, and SOX2 with expression noted in 2, 0.5, and 3.5% of iMS cells respectively, but no expression was detected in AdMSCs (Fig. 2E). In addition to these transcription factors, we also evaluated surface expression of TRA-1-60 and SSEA4. Both proteins were uniformly expressed on iPSCs and absent in AdMSCs [fig. S4F(i)] and adipocytes [fig. S4F(ii)]. Although TRA-1-60 was absent in iMS cells, most (78%) expressed SSEA4 but rarely (<1%) coexpressed OCT4 and NANOG [fig. S4F(i)].

MSCs can be induced to differentiate in vitro into various cell lineages in response to specific cytokines and culture conditions. To evaluate the in vitro plasticity of human iMS cells, we induced their differentiation along with matched AdMSCs and primary adipocytes, into bone, fat, and cartilage, as well as into other mesodermal Matrigel tube-forming assays for endothelial cells (CD31) and pericytes (PDGFR) and muscle (MYH, myosin heavy chain; SMA, smooth muscle actin), endodermal (hepatocyte; HNF4, hepatocyte nuclear factor ), and neuroectodermal (TUJ1; neuron specific class III beta tubulin) lineages (Fig. 2F and fig. S4G). Whereas primary adipocytes remained as such and were resistant to transdifferentiation, iMS cells and AdMSCs showed comparable differentiation potential with the notable exception that only iMS cells generated pericyte-lined endothelial tubes in Matrigel. In keeping with these findings, relative to AdMSCs, iMS cells showed permissive epigenetic marks at pericyte genes [increased H3K4me3 and H3K27Ac; EPHA2 and MCAM; fig. S4H(i); and reduced CpG methylation; NOTCH1, SMAD7, TIMP2, AKT1, and VWF; fig. S4H(ii)]. Together with the notable differences in epigenetic profiles, these functional differences and low-level expression of pluripotency genes in iMS cell subsets suggested that these cells could be more amenable than matched AdMSCs to respond to developmental cues in vivo.

To evaluate spontaneous teratoma formation and in vivo plasticity of iMS cells, we tagged these cells and their matched AdMSCs with a dual lentiviral reporter, LeGO-iG2-Luc2 (28), that expresses both green fluorescent protein (GFP) and luciferase under the control of the cytomegalovirus promoter (Fig. 3A). To test teratoma-initiating capacity, we implanted tagged cells under the right kidney capsules of NOD Scid Gamma (NSG) mice (n = 3 per treatment group) after confirming luciferase/GFP expression in cells in culture (fig. S5, A and B). Weekly bioluminescence imaging (BLI) confirmed retention of cells in situ [Fig. 3B(i)] with progressive reduction in signal over time [Fig. 3B(ii)] and the absence of teratomas in kidneys injected with either AdMSCs or iMS cells [Fig. 3B(iii)]. Injection of equivalent numbers of iPS cells and iPS + iMS cell mixtures (1:49) to approximate iMS fraction expressing pluripotency markers led to spontaneous tumor formation in the same timeframe [Fig. 3B(iii)].

(A) Generation of luciferase/GFP-reporter AdMSCs and iMS cells, and assessment of their in vivo function. (B) Assessment of teratoma initiating capacity; (i) bioluminescence images at 0, 2, 6, and 8 weeks after implantation of 1 106 matched AdMSCs and iMS cells (P2; RM0057; n = 2 per group) under the right kidney capsules. (ii) Quantification of bioluminescence. (iii) Gross kidney morphology 8 weeks following subcapsular implantation of cells (R) or vehicle control (L). (C) Assessment of in vivo plasticity in a posterior-lateral intertransverse lumbar fusion model; (i) bioluminescence images following lumbar implantation of 1 106 matched AdMSCs or iMS cells (P2; RM0038; n = 3 per group) at 1 and 365 days after transplant. (ii) Quantification of bioluminescence. (iii) Tissues (bone, cartilage, muscle, and blood vessels) harvested at 6 months after implantation stained with (left) hematoxylin and eosin or (right) lineage-specific anti-human antibodies circles/arrows indicate regions covering GFP and lineage markerpositive cells. Corresponding graphs show donor cell (GFP+) contributions to bone, cartilage, muscle, and blood vessels as a fraction of total (DAPI+) cells in four to five serial tissue sections. Bars indicate confidence interval, n = 3. Photo Credit: Avani Yeola, UNSW Sydney.

To evaluate whether iMS cells survived and integrated with damaged tissues in vivo, we implanted transduced human iMS cells and matched AdMSCs controls into a posterior-lateral intertransverse lumbar fusion mouse model (Fig. 3A) (29). Cells were loaded into Helistat collagen sponges 24 hours before implantation into the posterior-lateral gutters adjacent to decorticated lumbar vertebrae of NSG mice (n = 9 iMS and n = 9 AdMSC). Cell retention in situ was confirmed by intraperitoneal injection of d-luciferin (150 mg/ml) followed by BLI 24 hours after cell implantation, then weekly for the first 6 weeks and monthly up to 12 months from implantation [Fig. 3C(i)]. The BLI signal gradually decreased with time but persisted at the site of implantation at 12 months, the final assessment time point [Fig. 3C(ii)]. Groups of mice (n = 3 iMS and n = 3 AdMSC) were euthanized at 3, 6, and 12 months and tissues harvested from sites of cell implantation for histology and immunohistochemistry [Fig. 3C(iii)]. Although implanted iMS cells and AdMSCs were present and viable at sites of implantation at 3 months, there was no evidence of lineage-specific gene expression in donor human cells (fig. S5C). By contrast, at 6 months after implantation, GFP+ donor iMS cells and AdMSCs were shown to contribute to new bone (BMP2), cartilage (SOX9), muscle (MYH), and endothelium (CD31) at these sites of tissue injury [Fig. 3C(iii)]. The proportion of donor cells expressing lineage-specific markers in a corresponding tissue section was significantly higher in iMS cells compared with matched AdMSCs at 6 months [Fig. 3C(iii) and table S2] as well as 12 months (fig. S5, E and D, and table S2). There was no evidence of malignant growth in any of the tissue sections or evidence of circulating implanted GFP+ iMS cells or AdMSCs (fig. S5E). Together, these data show that implanted iMS cells were not teratogenic, were retained long term at sites of implantation, and contributed to regenerating tissues in a context-dependent manner with greater efficiency than matched AdMSCs.

Although appropriate to assess in vivo plasticity and teratogenicity of implanted cells, the posterior-lateral intertransverse lumber fusion mouse model is not suited to address the question of tissue-specific differentiation and repair in vivo. To this end, we used a muscle injury model (30) where necrosis was induced by injecting 10 M cardiotoxin (CTX) into the left tibialis anterior (TA) muscle of 3-month-old female severe combined immunodeficient (SCID)/Beige mice. CTX is a myonecrotic agent that spares muscle satellite cells and is amenable to the study of skeletal muscle regeneration. At 24 hours after injury, Matrigel mixed with either 1 106 iMS cells or matched AdMSCs (or no cells as a control) was injected into the damaged TA muscle. The left (injured) and right (uninjured control) TA muscles were harvested at 1, 2, or 4 weeks after injury to assess the ability of donor cells to survive and contribute to muscle regeneration without ectopic tissue formation (Fig. 4A; cohort A). Donor human iMS cells or AdMSCs compete with resident murine muscle satellite cells to regenerate muscle, and their regenerative capacity is expected to be handicapped not only by the species barrier but also by having to undergo muscle satellite cell commitment before productive myogenesis. Recognizing this, a cohort of mice was subject to a second CTX injection, 4 weeks from the first injury/cell implantation followed by TA muscle harvest 4 weeks later (Fig. 4A; cohort B).

(A) Generation of iMS and AdMSCs and their assessment in TA muscle injury model. (B) (i) Confocal images of TA muscle stained for human CD56+ satellite cells (red) and laminin basement membrane protein (green; mouse/human). Graph shows donor hCD56+ satellite cell fraction for each treatment group. (ii) Confocal images of TA muscle harvested at 4 weeks and stained for human spectrin (red) and laminin (green; mouse/human). For each treatment, the left panel shows a tile scan of the TA muscle and the right panel a high magnification confocal image. Graph shows contribution of mouse (M), human (H), or chimeric (C) myofibers in three to five serial TA muscle sections per mouse (n = 3 mice per treatment group). (C) Confocal images of TA muscle 4 weeks following re-injury with CTX, stained for human spectrin (red) and laminin (green; mouse/human). For each treatment, left panel shows a tile scan of the TA muscle, upper right panel a low-magnification image, and lower right panel a high magnification image of the area boxed above. Graph shows contribution of mouse (M), human (H), or chimeric (C) myofibers in three to five serial TA muscle sections per mouse (n = 3 mice per treatment group). Graph bars indicate confidence interval. *P < 0.05, **P < 0.01, and ***P < 0.001 (linear mixed model). Photo credit: Avani Yeola, UNSW Sydney.

In tissue sections harvested from cohort A, donor-derived muscle satellite cells (31) [hCD56 (Thermo Fisher Scientific, MA5-11563)+; red] were evident in muscles implanted with both iMS cells and AdMSCs at each time point but were most numerous at 2 weeks after implantation [Fig. 4B(i) and fig. S6A]. The frequency of hCD56+ cells relative to total satellite cells [sublaminar 4,6-diamidino-2-phenylindolepositive (DAPI+) cells] was quantified in three to five serial sections of TA muscles per mouse in each of three mice per treatment group and was noted to be higher following the implantation of iMS cells compared with AdMSCs at all time points [week 1, 5.6% versus 2.4%; week 2, 43.3% versus 18.2%; and week 4, 30.7% versus 14.6%; Fig. 4B(i), table S2, and fig. S6A]. Donor cell contribution to regenerating muscle fibers was also assessed by measuring human spectrin (32) costaining with mouse/human laminin [(33) at 4 weeks (Fig. 4B(ii)]. At least 1000 myofibers from three to five serial sections of TA muscles for each of three mice in each treatment group were scored for human [H; hSpectrin+ (full circumference); laminin+], murine (M; mouse; hSpectrin; laminin+), or mouse/human chimeric [C; hSpectrin+ (partial circumference); laminin+] myofibers. Although none of the myofibers seen in cross section appeared to be completely human (i.e., donor-derived), both iMS cells and AdMSCs contributed to chimeric myofibers [Fig. 4B(ii)]. iMS cell implants contributed to a substantially higher proportion of chimeric fibers than AdMSC implants (57.7% versus 30.7%; table S2). In cohort B, TA muscles were allowed to regenerate following the initial CTX injection/cell implantation, and re-injured 4 weeks later with a repeat CTX injection. In these mice, although total donor cell contributions to myofibers in TA muscles harvested 4 weeks after re-injury were comparable to that observed in cohort A, there were no myofibers that appeared to be completely human (Fig. 4C). There were substantially more human myofibers following iMS cell implants than with AdMSCs (9.7% versus 5.4%; table S2). There was no evidence of ectopic tissue formation in TA muscles following implantation of either iMS cells or AdMSCs in either cohort.

To assess the physiological properties of muscles regenerated with human myofibers, we performed tetanic force contractions in extensor digitorum longus (EDL) muscles following the schema shown in Fig. 4A. Tetanic forces evoked by electrical pulses of various stimulus frequencies were not significantly different between the experimental cohorts or between the experimental cohorts and control animals [fig. S6B, (i) to (iii)]. However, when challenged with a sustained train of electrical pulses [fig. S6C(i)], the iMS group demonstrated significantly greater absolute [fig. S6C(ii)] and specific [fig. S6C(iii)] forces over a 3- to 6-s period. Together, these data showed that iMS cells had the capacity to respond appropriately to the injured environment and contribute to tissue-specific regeneration without impeding function.

We have optimized a protocol, originally designed for mouse osteocytes, to convert human primary adipocytes into iMS cells. We show that these long-term repopulating cells regenerate tissues in vivo in a context-dependent manner without generating ectopic tissues or teratomas.

PDGF-AB, AZA, and serum are indispensable ingredients in reprograming media, but the underlying reasons for their cooperativity and the observed dose-response variability between patients are not known. PDGF-AB is reported to bind and signal via PDGFR- and PDGFR- but not PDGFR- subunits (21). Mouse osteocytes and human adipocytes lack PDGFR, although surface expression was detectable as cells transition during reprogramming [mouse; day 2 of 8 (14) and human day 21 of 25]. However, these cells express PDGFR (14). Given that PDGFR inhibition attenuates iMS cell production in both mice (14) and humans, a degree of facilitated binding of PDGF-AB to PDGF- subunits or signaling through a noncanonical receptor is likely to occur, at least at the start of reprogramming. PDGF-Bcontaining homo- and heterodimers are potent mitogens that increase the pool of undifferentiated fibroblasts and preosteoblasts with rhPDGF-BB used in the clinic to promote healing of chronic ulcers and bone regeneration (34). However, the unique characteristics of PDGF-AB but not PDGF-BB or PDGF-AA that facilitate reversal and plasticity of cell identity in combination with AZA and serum (14) remain unknown.

PDGF-AB was replenished in culture throughout the reprogramming period, but AZA treatment was limited to the first 2 days for both mouse osteocyte and human adipocyte cultures. DNA replication is required for incorporation of AZA into DNA (35) and hence DNA demethylation is unlikely to be an initiating event in the conversion of terminally differentiated nonproliferating cells such as osteocytes and mature adipocytes. However, the majority of intracellular AZA is incorporated into RNA, which could directly affect the cellular transcriptome and proteome as an early event (36, 37). It is feasible that subsequent redistribution of AZA from RNA to DNA occurs when cells replicate resulting in DNA hypomethylation as a later event (38).

In the absence of serum, we could neither convert primary human adipocytes into iMS cells nor perpetuate these cells long term in culture. The efficiency of conversion and expansion was significantly higher with human versus FCS and highest with AS. The precise serum factor(s) that are required for cell conversion in conjunction with PDGF-AB and AZA are not known. The volumes of blood (~50 ml 2) and subcutaneous fat (5 g) that we harvested from donors were not limiting to generate sufficient numbers of P2 iMS cells (~10 106) for in vivo implantation and are in the range of cell numbers used in prospective clinical trials using mesenchymal precursor cells for chronic discogenic lumbar back pain (NCT02412735; 6 106) and hypoplastic left heart syndrome (NCT03079401; 20 106).

Our motivation was to optimize a protocol that could be applied to primary uncultured and easily accessible cells for downstream therapeutic applications, and adipose tissue satisfied these criteria. We have not surveyed other human cell types for their suitability for cell conversion using this protocol. It would be particularly interesting to establish whether tissue-regenerative properties of allogeneic mesenchymal precursor populations that are currently in clinical trials could be boosted by exposure to PDGF-AB/AZA. However, given that iMS cells and MSCs share stromal cell characteristics, identifying a unique set of cell surface markers that can distinguish the former is a priority that would assist in future protocol development and functional assessment of iMS cells.

Producing clinical-grade autologous cells for cell therapy is expensive and challenging requiring suitable quality control measures and certification. However, the advent of chimeric antigen receptor T cell therapy into clinical practice (39) has shown that production of a commercially viable, engineered autologous cellular product is feasible where a need exists. Although there were no apparent genotoxic events in iMS cells at P2, ex vivo expansion of cells could risk accumulation of such events and long-term follow-up of ongoing and recently concluded clinical trials using allogeneic expanded mesenchymal progenitor cells will be instructive with regard to their teratogenic potential. The biological significance of the observed expression of pluripotency-associated transcription factors in 2 to 3% of murine and human iMS cells is unknown and requires further investigation. However, their presence did not confer teratogenic potential in teratoma assays or at 12-month follow-up despite persistence of cells at the site of implantation. However, this risk cannot be completely discounted, and the clinical indications for iMS or any cell therapy require careful evaluation of need.

In regenerating muscle fibers, it was noteworthy that iMS cells appeared to follow canonical developmental pathways in generating muscle satellite cells that were retained and primed to regenerate muscle following a second muscle-specific injury. Although iMS cells were generated from adipocytes, there was no evidence of any adipose tissue generation. This supports the notion that these cells have lost their native differentiation trajectory and adopted an epigenetic state that favored response to local differentiation cues. The superior in vivo differentiation potential of iMS cells vis--vis matched AdMSCs was consistent with our data showing that despite the relatively minor transcriptomic differences between these cell types, the epigenetic state of iMS cells was better primed for systems development. Another clear distinction between iMS cells and AdMSCs was the ability of the former to produce CD31+ endothelial tube-like structures that were enveloped by PDGFR+ pericytes. An obvious therapeutic application for iMS cells in this context is vascular regeneration in the setting of critical limb ischemia to restore tissue perfusion, an area of clear unmet need (40).

An alternative to ex vivo iMS cell production and expansion is the prospect of in situ reprogramming by local subcutaneous administration of the relevant factors to directly convert subcutaneous adipocytes into iMS cells, thereby eliminating the need for ex vivo cell production. AZA is used in clinical practice and administered as a daily subcutaneous injection for up to 7 days in a 28-day cycle, with responders occasionally remaining on treatment for decades (41). Having determined the optimal dose of AZA required to convert human adipocytes into iMS cells in vitro (2 days, 5 M), the bridge to ascertaining the comparable in vivo dose would be to first measure levels of AZA incorporation in RNA/DNA following in vitro administration and match the dose of AZA to achieve comparable tissue levels in vivo. A mass spectrometrybased assay was developed to measure in vivo incorporation of AZA metabolites (AZA-MS) in RNA/DNA and is ideally suited to this application (38). The duration of AZA administration for adipocyte conversion was relatively short (i.e., 2 days), but PDGF-AB levels were maintained for 25 days. One mechanism of potentially maintaining local tissue concentrations would be to engineer growth factors to bind extra cellular matrices and be retained at the site of injection. Vascular endothelial growth factor A (VEGF-A) and PDGF-BB have recently been engineered with enhanced syndecan binding and shown to promote tissue healing (42). A comparable approach could help retain PDGF-AB at the site of injection and maintain local concentrations at the required dose. While our current data show that human adipocytederived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth, these approaches are worth considering as an alternative to an ex vivo expanded cell source in the future.

Extended methods for cell growth and differentiation assays and animal models are available in the Supplementary Materials, and antibodies used are detailed in the relevant sections.

The primary objective of this study was to optimize conditions that were free of animal products for the generation of human iMS cells from primary adipocytes and to characterize their molecular landscape and function. To this end, we harvested subcutaneous fat from donors across a broad age spectrum and used multiple dose combinations of a recombinant human growth factors and a hypomethylating agent used in the clinic and various serum types. We were particularly keen to demonstrate cell conversion and did so by live imaging and periodic flow cytometry for single-cell quantification of lipid loss and gain of stromal markers. Using our previous report generating mouse iMS cells from osteocytes and adipocytes as a reference, we first characterized the in vitro properties of human iMS cells including (i) long-term growth, (ii) colony-forming potential, (iii) in vitro differentiation, and (iv) molecular landscape. Consistent with their comparative morphology, cell surface markers, and behavioral properties, the transcriptomes (RNA sequencing) were broadly comparable between iMS cells and matched AdMSCs, leading to investigation of epigenetic differences [Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) histone chromatin immunoprecipitation sequencing (ChIP-seq), and RRBS for DNA methylation differences] that might explain properties that were unique to iMS cells (expression of pluripotency factors, generation of endothelial tubes in vitro with pericyte envelopes, and in vivo regenerative potential). Context-dependent in vivo plasticity was assessed using a tissue injury model that was designed to promote bone/cartilage/muscle/blood vessel contributions from donor cells and simultaneously assess the absence of ectopic/malignant tissue formation by these cells (labeled and tracked in vivo using a bioluminescence/fluorescence marker). Tissue-specific regeneration and the deployment of canonical developmental pathways were assessed using a specific muscle injury model, and donor cell contributions in all injury models were performed on multiple serial tissue sections in multiple mice with robust statistical analyses (see below). Power calculations were not used, samples were not excluded, and investigators were not blinded. Experiments were repeated multiple times or assessments were performed at multiple time points. Cytogenetic and Copy Number Variation (CNV) analyses were performed on iMS and AdMSCs pretransplant, and their teratogenic potential was assessed both by specific teratoma assays and long-term implantation studies.

Subcutaneous fat and blood were harvested from patients undergoing surgery at the Prince of Wales Hospital, Sydney. Patient tissue was collected in accordance with National Health and Medical Research Council (NHMRC) National Statement on Ethical Conduct in Human Research (2007) and with approval from the South Eastern Sydney Local Health District Human Research Ethics Committee (HREC 14/119). Adipocytes were harvested as described (43). Briefly, adipose tissue was minced and digested with 0.2% collagenase type 1 (Sigma-Aldrich) at 37C for 40 min and the homogenized suspension passed through a 70-m filter, inactivated with AS, and centrifuged. Primary adipocytes from the uppermost fatty layer were cultured using the ceiling culture method (44) for 8 to 10 days. AdMSCs from the stromal vascular pellet were cultured in MEM + 20% AS + penicillin (100 g/ml) and streptomycin (250 ng/ml), and 200 mM l-glutamine (complete medium).

Adherent mature adipocytes were cultured in complete medium supplemented with AZA (R&D systems; 5, 10, and 20 M; 2 days) and rhPDGF-AB (Miltenyi Biotec; 100, 200, and 400 ng/ml; 25 days) with medium changes every 3 to 4 days. For inhibitor experiments, AG1296 was added for the duration of the culture. Live imaging was performed using an IncuCyte S3 [10 0.25numerical aperture (NA) objective] or a Nikon Eclipse Ti-E (20 0.45-NA objective). Images were captured every 30min for a period of 8 days starting from day 15. Twelve-bit images were acquired with a 1280 1024 pixel array and analyzed using ImageJ software. In vitro plasticity was determined by inducing the cells to undergo differentiation into various cell types using differentiation protocols adapted from a previous report (45).

Animals were housed and bred with approval from the Animal Care and Ethics Committee, University of New South Wales (UNSW; 17/30B, 18/122B, and 18/134B). NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) and SCID/Beige (C.B-Igh-1b/GbmsTac-Prkdcscid-Lystbg N, sourced from Charles River) strains were used as indicated. The IVIS Spectrum CT (Perkin Elmer) was used to capture bioluminescence. Briefly, 15 min after intraperitoneal injection of d-luciferin (150 mg/kg), images were acquired for 5 min and radiance (photon s1 cm2 sr1) was used for subsequent data analysis. The scanned images were analyzed using the Living Image 5.0 software (Perkin Elmer).

Teratoma assays (46) were performed on 3- to 4-month-old female NSG mice. Lentiviral-tagged cells (5 105) in 20 l of phosphate-buffered saline containing 80% Matrigel were injected under the right kidney capsule using a fine needle (26 gauges) and followed weekly by BLI until sacrifice at week 8. Both kidneys were collected, fixed in 4% paraformaldehyde (PFA) for 48 hours, embedded in optimal cutting temperature compound (OCT), cryosectioned, and imaged for GFP.

Posterior-lateral intervertebral disc injury model (29). Lentiviral-tagged (28) AdMSCs (1 106) or iMS cells were loaded onto Helistat collagen sponges and implanted into the postero-lateral gutters in the L4/5 lumbar spine region of anesthetized NSG mice following decortication of the transverse processes. Animals were imaged periodically for bioluminescence to track the presence of transplanted cells. At 3, 6, or 12 months, mice were euthanized, and spines from the thoracic to caudal vertebral region, including the pelvis, were removed whole. The specimens were fixed in 4% PFA for 48 hours, decalcified in 14% (w/v) EDTA, and embedded in OCT.

Muscle injury model (47). The left TA and EDL muscles of 3- to 4-month-old female SCID/Beige mice were injured by injection with 15 l of 10 M CTX (Latoxan). Confocal images of three to four serial sections (TA) per mouse were captured by Zen core/AxioVision (Carl Zeiss) and visualized by ImageJ with the colocalization and cell counter plugins [National Institutes of Health; (48)]. Tetanic force contractions were performed on EDL muscles (49).

Total RNA was extracted using the miRNeasy Mini Kit (Qiagen) according to manufacturers instructions, and 200 ng of total RNA was used for Illumina TruSeq library construction. Library construction and sequencing was performed by Novogene (HK) Co. Ltd. Raw paired-end reads were aligned to the reference genome (hg19) using STAR (https://github.com/alexdobin/STAR), and HTSeq (50) was used to quantify the transcriptomes using the reference refFlat database from the UCSC Table Browser (51). The resulting gene expression matrix was normalized and subjected to differential gene expression using DeSeq2 (52). Normalized gene expression was used to compute and plot two-dimensional principal components analysis, using the Python modules sklearn (v0.19.1; https://scikit-learn.org/stable/) and Matplotlib (v2.2.2; https://matplotlib.org/), respectively. Differentially expressed genes (log2 fold change |1|, adjusted P < 0.05) were the input to produce an unsupervised hierarchical clustering heat map in Partek Genomics Suite software (version 7.0) (Partek Inc., St. Louis, MO, USA). Raw data are available using accession GSE150720.

ChIP was performed as previously described (53) using antibodies against H3K27Ac (5 g per IP; Abcam, ab4729), H3K4Me3 (5 g per IP; Abcam ab8580), and H3K27Me3 (5 g per IP; Diagenode, C15410195). Library construction and sequencing were performed by Novogene (HK) Co. Ltd. Paired-end reads were aligned to the hg38 genome build using Burrows Wheeler Aligner (BWA) (54) duplicate reads removed using Picard (http://broadinstitute.github.io/picard/), and tracks were generated using DeepTools bamCoverage (https://deeptools.readthedocs.io/en/develop/). Peaks were called using MACS2 (55) with the parameter (P = 1 109). Differentially bound regions between the AdMSC and iMS were calculated using DiffBind (http://bioconductor.org/packages/release/bioc/vignettes/DiffBind/inst/doc/DiffBind.pdf) and regions annotated using ChIPseeker (56). Raw data are available using accession GSE151527. Adipocyte ChIP data were downloaded from Gene Expression Omnibus (GEO); accession numbers are as follows for the three histone marks: GSM916066, GSM670041, and GSM772771.

Total genomic DNA was extracted using the DNA MiniPrep Kit (Qiagen), and RRBS library construction and sequencing were performed by Novogene (HK) Co. Ltd. Raw RRBS data in fastq format were quality and adapter trimmed using trim_galore (0.6.4) with rrbs parameter (www.bioinformatics.babraham.ac.uk/projects/trim_galore). The trimmed fastq files were then aligned to a bisulfite-converted genome (Ensembl GRCh38) using Bismark (2.3.5), and methylation status at each CpG loci was extracted (57). The cytosine coverage files were converted to BigWig format for visualization. Differentially methylated cytosines (DMCs) and DMRs were identified using methylKit (1.10) and edmr (0.6.4.1) packages in R (3.6.1) (58, 59). DMCs and DMRs were annotated using ChIPseeker (56), and pathway enrichment was performed as detailed below. Raw data are available using accession number GSE151527. Adipocyte RRBS data were downloaded from GEO: GSM2342293 and GSM2342392.

IPA (Qiagen) was used to investigate enrichment in molecular and cellular functions, systems development and function, and canonical pathways.

Statistical analysis was performed in SAS. For the dose-optimization experiments (Fig. 1), a linear mixed model with participant-level random effects was used to estimate maximum time by dose level and age group. A linear mixed model with participant-level random effects was used to analyze statistical differences in lineage contribution outcomes between treatment groups (Fig. 3) and at different time points posttransplant, to estimate the percentage of cells by treatment and lineage. For the in vivo regeneration experiment (Fig. 4), a linear model was used to model the percent of cells over time for each group. Quadratic time terms were added to account for the observed increase from 1 to 2 weeks and decrease from 2 to 4 weeks. In the muscle regeneration experiment, a linear model was applied to cohort A and cohort B, to estimate and compare percent cells by treatment and source. Statistical modeling data are included in table S2.

Acknowledgments: We are indebted to the patients who donated tissue to this project. We thank E. Cook (Prince of Wales Private Hospital), B. Lee (Mark Wainwright Analytical Centre, UNSW Sydney), and technicians at the UNSW BRC Facility for assistance with sample and data collection and animal care; Y. Huang for technical assistance; and A. Unnikrishnan and C. Jolly for helpful discussions and critical reading of the manuscript. We acknowledge the facilities and scientific and technical assistance of the National Imaging Facility, a National Collaborative Research Infrastructure Strategy (NCRIS) capability, at the BRIL (UNSW). The STRO-1 antibody was a gift from S. Gronthos, University of Adelaide, Australia. Funding: We acknowledge the following funding support: A.Y. was supported by an Endeavour International Postgraduate Research scholarship from the Australian Government. S.S. is supported by an International Postgraduate Student scholarship from UNSW and the Prince of Wales Clinical School. P.S. is supported by an International Postgraduate Student scholarship from UNSW. M.L.T. and D.D.M. acknowledge funding from St. Vincents Clinic Foundation and Arrow BMT Foundation. K.A.K. acknowledges funding from Australian Research Council (FT180100417). J.M. is supported, in part, by the Olivia Lambert Foundation. M.K. is supported by a NHMRC Program Grant (APP1091261) and NHMRC Principal Research Fellowship (APP1119152). L.B.H. acknowledges funding from MTPConnect MedTech and Pharma Growth Centre (PRJ2017-55 and BMTH06) as part of the Australian Governmentfunded Industry Growth Centres Initiative Programme and The Kinghorn Foundation. D.B. is supported by a Peter Doherty Fellowship from the National Health and Medical Research Council of Australia, a Cancer Institute NSW Early Career Fellowship, the Anthony Rothe Memorial Trust, and Gilead Sciences. R.M. acknowledges funding from Jasper Medical Innovations (Sydney, Australia). J.E.P., V.C., and E.C.H. acknowledge funding from the National Health and Medical Research Council of Australia (APP1139811). Author contributions: The project was conceived by V.C. and J.E.P., and the study design and experiments were planned by A.Y., V.C., and J.E.P. Most of the experiments and data analyses were performed by A.Y., guided and supervised by V.C. and J.E.P. S.S., R.A.O., C.A.L., D.C., F.Y., M.L.T., P.S., T.H., J.R.P., P.H., W.R.W., and V.C. performed additional experiments and data analyses, with further supervision from R.M., C.P., J.A.I.T., D.C., J.W.H.W., L.B.H., D.B., and E.C.H. Statistical analyses were performed by J.O. R.M., D.D.M., J.M., K.A.K., and M.K. provided critical reagents. The manuscript was written by A.Y., J.A.I.T., V.C., and J.E.P., and reviewed and agreed to by all coauthors. Competing interests: V.C. and J.E.P. are named inventors on a patent A method of generating cells with multi-lineage potential (US 9982232, AUS 2013362880). All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine - Science Advances

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