Researchers from the Murdochs Children Research Institute (MCRI) are developing new treatments for congenital heart disease that could enable children born with birth defects can regenerate the damaged organ.

In 2011, Prof. Enzo Porrello, who is nowhead of the Heart Regeneration Laboratory at the MCRI,demonstrated the regenerative properties of newborn mouse hearts at the University of Texas Southwestern Medical Centre. Prior to this research, the capacity of mammalian hearts to regenerate was a debated topic.

This sort of changed our thinking of what was possible in terms of stimulating the human heart to regenerate itself following damage, such as a heart attack, Porrello said, reported theAustralian. And I guess this also fuelled my own interest in my subsequent career in the area of regenerative medicine.

After hearing about cases where newborns recovered from massive heart attacks, Porrello began to explore the regenerative properties of human newborn hearts.

In 2017, Porrello and Prof. James Hudson manufactured living and beating heart tissues from stem cells in a laboratory at the University of Queensland.

Porrello said that although other scientists had grown heart muscle cells from stem cells, nobody had grown the cells as miniature complex three-dimensional tissues. Additionally, they were not able to grow such tissues in a format compliant to drug development, he said.

And thats really the technological breakthrough that we were able to make.

According to the Australian Institute of Health and Welfare, approximately nine out of every 1,000 babies born around the world will be born with congenital heart disease. In Australia, it is estimated that 2,400 babies are born with congenital heart disease annually, while in America, nearly one percent of all babies born are estimatedby the Centre For Disease Control to have the condition.

Porrello said that, at the moment, if a child develops heart failure and doesnt respond to standard frontline therapies, a heart transplant is their only option. Children in this situation are put on a transplant waiting list, and whilst waiting for a heart to become available, they are put on mechanical support.

Heart transplantation is limited by organ donor availability, and its also limited by the need for lifelong immunosuppression in those patients, Porrello said.

And so if were able to develop these bioengineered heart tissues from stem cells, this could potentially prevent or delay the need for heart transplantation in these very unwell individuals with end-stage heart failure.

Porrello said that the ultimate goal of his research is to harness the self-repairing capacity of the newborn heart and to develop drugs that waken the hearts dormant regenerative abilities so that the organ may repair itself after damage.

I would say that based on recent studies in the field in the past 10 years since we first made our discovery in mice, we are certainly getting closer, he said.

There is sort of proof of concept that this is possible now, at least in mice, and the question is whether or not we can now make that a therapeutic reality in humans.

The first step in creating these complex heart tissues is attaching special molecules to stem cells; these molecules trigger the cells to morph into heart muscle tissue. The heart tissues are then developed in a plastic culture dish that consists of 96 tiny wells.

The geometry of the well is designed in such a way that the heart tissues spontaneously form when the heart muscle cells are inserted into the well, Porrello said.

He said that within each well of the device are tiny elastic micropillars; the pillars function as elastic cantilevers since they are attached to the dish at only one end and extend horizontally to the dish. The heart muscle cells condense around these cantilevers to produce tiny miniature beating heart tissues that contract around the micropillar; every time the tissue contracts, the micropillar within it deflects.

Porrello said that the device enables researchers to measure the force that the tissues are generating, allowing them to observe how fast the tissues are beating and whether they display any irregularities in their heartbeat. These capabilities are useful for treatment testing because the effect that medication or genetic manipulations of stem cells have on the tissues heartbeat can be seen.

And so it serves as a pretty powerful platform for looking at drug responses, but also modelling genetic forms of heart disease.

Were actually now scaling up these tissues and growing very, very large bioengineered heart tissue patches that can be implanted onto the heart.

In an email to The Epoch Times, Porrello said in the future that, bioengineered heart tissue patches could be used to treat adults with heart failure, and alternative approaches are already being trialled.

Our bioengineered heart tissues could also be used to support the failing heart in adults with underlying heart disease.

Further studies are required to confirm that our bioengineered heart tissue patches are safe and effective in animal models before progressing to human trials. These pre-clinical safety and efficacy studies are underway.

He noted that although significant advances and a better understanding of the hearts regenerative mechanisms have been made in recent years, using this knowledge to develop a safe and effective drug is a slow process.

It typically takes 10 years and around $1 billion dollars to develop a new heart failure drug and take it all the way through to clinical approval. We are at the beginning of that journey.

We need to gain a better understanding of the fundamental biology underlying heart regeneration before we can develop effective treatments.

Porello is now applying his discoveries in a clinical context at theMCRIto reach his goal of regenerating human hearts. The regeneration research at the institute has two branches, the first focuses on studying diseases using lab-grown models of the heart muscle. The models are made using blood and tissue samples collected from sick children at the Royal Childrens Hospital in Melbourne.

He said that this branch of the research enables the team to model the genetic basis of the disease in any individual.

Were using this technology to model childhood heart disease, trying to understand its causes, and then using those genetic models of heart disease to test and develop therapeutic approaches to treat those conditions, he said.

Porrello said that the second branch of the research performed at the MCRI explores the regenerative approach to growing the very, very large bioengineered heart tissue patches. The researchers plan is to eventuallyimplant the patches into a heart to function as a biological assistance device that supports the function of the heart.

If it works, it would be transformative, Porrello said.

Stem cells have been used in medicine for more than fifty years, with the most common stem cell procedure currently beingbone marrow transplantsalso known as hematopoietic stem cell transplantsused to treat patients with blood cancers such asleukemiaand blood disorders such assickle cell diseaseandthalassemia.

More recently, skin grown from stem cells has been used to treat extensive burns, and stem cells from fat (adipose tissue) have been used as tissue fillers.

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Regenerative Properties of the Newborn Heart Offers Hope for Those With Congenital Heart Disease - The Epoch Times

After struggling with acne for years, White Orange founder Carishma Khubhani still had a hard time finding skin are products that worked for her and even when her acne cleared, she was worried that her skin may revert back to its old habits. I always wanted to have my own skin care line one day, said Khubani, who was a musician in Los Angeles before becoming a brand founder. [My dermatologist and esthetician] told me that the only things that have been proven to make a visible difference in your skin are vitamin C and retinol. Other vitamin C serums were expensive or unpleasant to use or simply didnt work which led her to create White Orange.

After three years of formulating, White Orange claims to bring on a new generation of vitamin C. Vitamin C is the king of skin care ingredients for good reason its proven to help with sun damage, dark spots, and even acne. But you might be surprised to learn that there are different types of vitamin C in the products you use. Most vitamin C products on the market (including the priciest products) use a form of vitamin C called L-ascorbic acid. Its a go-to because there have been so many clinical studies supporting its efficacy; however, the downside is that it can be irritating and unstable. (Stability ensures that the product retains its potency over time.) It's cheap and it's inexpensive and [brands who use it] want to maximize their profit margins to be able to pay all their overhead, Khubani says.

With this knowledge, Khubani chose to use a less-common form of vitamin C called tetra hexadecyl ascorbate, or BV-OSC. She claims its the most potent, yet stable form of vitamin C, and so far, the science looks promising: A study found that after an aqueous gel with 10% BV-OSC was applied to a group of patients over the span of two to 10 months, age spots, acne and skin redness all showed immense improvement.

In addition to tetrahexadecyl ascorbate, one of the most significant ingredients that influenced the name of the product is pith the white part of the orange (hence the brand name) which was included for its high concentration of vitamin C. Other ingredients include hyaluronic acid, ferulic acid, and vitamin E all superstar skin care ingredients proven to fight free radicals and help overall skin texture and brightness. White Orange also added orange stem cells, which feature their own exclusive proprietary complex, and a liposomal delivery system to help the ingredients penetrate more deeply into the skin.

Other products also use tetrahexadecyl ascorbate, like Sunday Riley C.E.O 15 Vitamin C Brightening Serum so what makes White Orange different? Its all in the delivery system. Many vitamin C products come in glass dropper bottles, so the product is exposed to light and air every time you use it, which allows the product to oxidize and become less effective. White Orange puts their product in a syringe-style bottle, so your product isnt exposed to air and you only pump out the amount you need, preserving the freshness of the serum. The formula is also vegan and cruelty-free.

Khubani recommends using the product before you apply your moisturizer and SPF and after you wash your face and potentially apply a toner. After washing my face with my CeraVe Hydrating facial cleanser, I used the White Orange serum and finished off with my trusty CeraVe moisturizer. The formula is very light and non-sticky and so far, the product seems to be very gentle and non-irritating (I have highly sensitive skin). I also really like the syringe bottle, which is travel-friendly and dispenses the perfect amount each time. I havent noticed any anti-aging or acne-preventing effects, but I would recommend trying this product if youre looking to add a gentle serum to a simple skincare routine and if you have sensitive skin, you can rest easy knowing this formula wont irritate.

Studies cited:

Telang P. S. (2013). Vitamin C in dermatology. Indian dermatology online journal, 4(2), 143146.

Al-Niaimi, F., & Chiang, N. (2017). Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications. The Journal of clinical and aesthetic dermatology, 10(7), 1417.

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Meet White Orange: The Vitamin C Skin Care Brand For Sensitive Skin - Bustle

FACT.MR

Over the coming years, the orthopedic navigation systems market is expected to experience significant growth due to rapid technological innovations, introduction of new orthopedic navigation products, rising cases of cardiovascular diseases, increased funding in R&D activities to improve orthopedic navigation product effectiveness, and rise in the prevalence of osteoarthritis.

United States, Rockville MD, Sept. 02, 2022 (GLOBE NEWSWIRE) -- Expanding at a high-value CAGR of 17%, the global demand for orthopedic navigation systems is projected to increase to a valuation of US$ 433.8 million by 2027, predicts Fact.MR, a market research and competitive intelligence provider.

By expressing three-dimensional computer images in comparative patient analysis, which is a feature of image-guided surgical systems, the orthopedic navigation system integrates information from pre-operative planning and intra-operative execution. These computer workstations for image-guided surgery include a surgical planning and display monitor, image-processing software, and a digitizing system.

As a result of bone spine damage to the spinal nerves, spinal cord, or neurological injury weakening, spinal injuries are the primary cause of mortality and morbidity. To reduce long-term functional disability, prompt medical and surgical care is essential, thereby driving the need for orthopedic navigation systems.

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Effective Results of Computer-assisted Navigation Systems

Other elements anticipated to influence the industry's revenue include associated benefits of computer-assisted surgeries (CAS), including low blood loss, shorter hospital stays, and simpler recovery.

Accurate implant alignment is made possible by CAS, which also enhances functioning, and quality-adjusted life years, and causes reduced discomfort, tissue damage, and problems.The aforementioned reasons are behind therising demand for minimally-invasive surgeries.

Story continues

Another factor that is anticipated to increase orthopedic navigation system demand is the development of technology in orthopedic surgical navigation procedures, as well as the rising prevalence of osteoarthritis, and increased investments in R&D.

Key Takeaways from Market Study

Demand for orthopedic navigation systems is expected to surge at a CAGR of 17% from 2022 to 2027.

Global orthopedic navigation system sales areanticipated to be driven by an increase in the use of minimally-invasive procedures and navigation software by doctors and surgeons due to the availability of affordable orthopedic navigationsolutions and greater awareness.

In terms of technology, optical navigation systems are superior to electromagnetic (EM) systems because they expose users to less radiation and provide greater accuracy during difficult operations, allowing surgeons to move accurately through the anatomy of a patient.

Sales of optical navigation systems are expected to balloon at a CAGR of 19% from 2022 to 2027.

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Winning Strategy

Top manufacturers of orthopedic navigation systems are concentrating on raising knowledge about these systems as well astheiruse and advantages among patients and medical professionals alike. By providing Continual Medical Education (CME) sessions, manufacturers of surgical navigation solutionsin developed nations have started to reach out to local communities.

As a result, more doctors and specialists are aware of the existence and application of orthopedic navigation systems. Furthermore, the 6- to 7-year warranty on commercially available orthopedic navigation devicesmakes the entire product sales cycle 7 years.

The market for orthopedic navigation systems is anticipated to expand rapidly over the forecast period due to increasing demand for technological assistance in orthopedic therapies.

Robotic-assisted surgical navigation robot NaoTrac was given CE mark clearance by Taiwan-based firm Brain Navi Biotechnology in November 2021. The company specialises in cutting-edge navigation robots.

Acuson Freestyle Elite ultrasound system, which can be used in conjunction with Artis angiography devices to provide quick and simple ultrasound guidance during interventional procedures, was introduced by Siemens Healthineers in March 2017.

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Segmentation of Orthopedic Navigation Systems Industry Research

By Technology :

Electromagnetic

Optical

Radiography

Others

By Application :

Knee

Spine

Hip

Joint Replacement

Others

By End User :

By Region :

North America

Latin America

Europe

East Asia

South Asia & Oceania

MEA

More Valuable Insights on Offer

Fact.MR, in its new offering, presents an unbiased analysis of the global orthopedic navigation systems market, presenting historical demand data (2017-2021) and forecast statistics for the period of 2022-2027.

The study divulges essential insights on the market on the basis of technology (electromagnetic, optical, radiography, others), application (knee, spine, hip, joint replacement, others), and end user (hospitals, clinics, ambulatory surgical centers, others), across five major regions of the world (North America, Europe, Asia Pacific, Latin America, and MEA).

Check out more related studies published by Fact.MR Research:

Orthopedic Braces and Support System Market:The global orthopedic braces and support system market was valued at aroundUS$ 3 Bnin 2020, which amounts to around11%share of the overall orthopedic devices market. Sales of orthopedic braces and support systems are slated to accelerate at a CAGR of6%to topUS$ 5.5 Bnby 2031. Demand for knee braces and supports is set to increase at a CAGR of5%across the assessment period of 2021 to 2031.

Orthopedic Power Tools Market:The global orthopedic power tools market is estimated atUSD 2.2 Billionin 2022 and is forecast to surpassUSD 3.5 Billionby 2032, growing at a CAGR of4.8%from 2022 to 2032.North America orthopedic power tools market accounts for the largest market share of24.8%.The escalating online presence of players with a strong distribution network coupled with well-established healthcare infrastructure is one of the key factors fueling the market growth.

Orthopedic Footwear Market:The global orthopedic footwear market is majorly driven by rise in the number of accidents, which is the major cause of orthopedic injury. In addition to this, increase in the availability as well as variability of orthopedic footwear in various applications also promotes the market growth. In context of this, about 6% of the U.S. population has foot injuries, bunions and flat feet or fallen arches each year. About 60% of U.S. population older than 17 are suffering from foot and ankle related injuries, sprains and strains of the ankle.

Bone Biopsy Systems Market:The global bone biopsy systems market is set to enjoy a valuation ofUS$ 227.6 millionin 2022 and expand at aCAGR of 6%to reachUS$ 408.9 millionby the end of 2032.Sales of bone biopsy systems accounted for more than30%of the global bone biopsy market at the end of 2021.Bone biopsy and bone marrow biopsy sampling have been one of the most painful experiences for patients. Efforts towards reducing this pain has led to the development of powered bone biopsy systems with increased efficiency.

Bone Marrow Processing Systems Market:A bone marrow processing system is a functionally closed, sterile system designed for automatically isolating and concentrating stem cells derived from donated bone marrow aspirate. Rising applications of bone marrow transplant procedures and bone marrow donation procedures used in the treatment of bone marrow cancers, such as acute leukemia, multiple myeloma, immune deficiency disorders, aplastic anemia, spinal fusions, lymphomas, non-union fractures, osteonecrosis and other rare genetic diseases of the bone marrow, is the primary driver in the market.

Bone Growth Stimulator Market:Bone growth stimulator market was nearly worthUS$ 1.8Bn in 2020 and is anticipated to expand1.6xover the forecast period, anticipated to reach a valuation ofUS$ 3Bn by 2031. In the short-run, bone growth stimulators revenue is likely to topUS$ 1.9Bn by 2022.The market for bone growth stimulators is dominated by North America. This is mostly due to the region's expanding elderly population and the growing burden of orthopedic illnesses. As of 2031, the U.S is expected to register a CAGR worth 5%.

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Increasing Road Accidents and Fall Injuries among Aged Population Primarily Driving Need for Orthopedic Navigation Systems: Fact.MR Analysis - Yahoo...

MENLO PARK, Calif. and SINGAPORE, Sept. 02, 2022 (GLOBE NEWSWIRE) -- ASLAN Pharmaceuticals (Nasdaq:ASLN), a clinical-stage, immunology focused biopharmaceutical company developing innovative treatments to transform the lives of patients, today announced Dr Carl Firth, CEO, is scheduled to give an in-person company presentation at the H.C. Wainwright 24th Annual Global Investment Conference on Monday, September 12, 2022, at 10:30 am ET. The conference will be held from September 12 to 14, 2022, virtually and in-person at the Lotte New York Palace Hotel.

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ASLAN Pharmaceuticals to Present at H.C. Wainwright 24th Annual Global Investment Conference

WESTLAKE VILLAGE, Calif., Sept. 02, 2022 (GLOBE NEWSWIRE) -- Arcutis Biotherapeutics, Inc. (Nasdaq: ARQT), an early-stage commercial company focused on developing meaningful innovations in immuno-dermatology, today announced that Neha Krishnamohan has been appointed to the Arcutis Board of Directors and as a member of the audit committee. Following the appointment, the Board will be composed of 10 directors.

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ORION CORPORATION STOCK EXCHANGE RELEASE – OTHER INFORMATION DISCLOSED ACCORDING TO THE RULES OF THE EXCHANGE2 SEPTEMBER 2022 at 17.30 EEST

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Prosecutor appealed the district court's decision to dismiss the charges pressed against a member of Orion's Board of Directors for a suspected...

City of Hope recently shared significant news at the 24th Annual AIDS Conference about a patient treated in 2019 whose HIV has been in remission. The man had been living with HIV for 31 years before coming to City of Hope with another grave diagnosisacute myeloid leukemia.One of the best hopes for long-term remission of acute myeloid leukemia (AML) is a stem cell transplant, and City of Hope has one of the nations leading transplant programs, having performed more than 17,000 transplants since 1976. In addition, the institution is at the forefront of using transplants to treat older adults with blood cancers, including increasing efficacy and safety in those over 60 and those with comorbidities, like the then 63-year-old City of Hope patient with HIV. The research was presented by Jana K. Dickter, M.D., City of Hope associate clinical professor in the Division of Infectious Diseases.

City of Hope hematologist Ahmed Aribi, M.D., assistant professor in the Division of Leukemia, prepared the patient for an allogeneic blood stem cell transplant with a chemotherapy-based, reduced-intensity regimen developed for treatment of older patients with blood cancers. Reduced-intensity chemotherapy makes the transplant more tolerable for older patients and reduces the potential for transplant-related complications from the procedure.

Aribi and his team worked with City of Hopes Unrelated Donor BMT Program directed by Monzr M. Al Malki, M.D. to find a donor who was a perfect match for the patient and had the rare genetic mutation, homozygous CCR5 Delta 32, which is found in just 1 to 2% of the general population.

People who have this mutation have a resistance to acquiring HIV. CCR5 is a receptor on CD4+ immune cells, and most strains of HIV use that receptor to enter and attack the immune system. But the CCR5 mutation blocks that pathway, which stops HIV from replicating.

After this successful transplant for both AML and HIV, the patient has been in remission for HIV since stopping ART in March 2021. While this outcome has happened in three other patients, the City of Hope patient was both the oldest to undergo a transplant with HIV and leukemia and go into remission for both. He had also lived with HIV the longest 31 years.

The City of Hope patient is another major advancement. It demonstrates that research and clinical care developed and led at City of Hope are changing the meaning of an HIV diagnosis for patients across the United States and the world, said John Zaia, M.D., director of City of Hopes Center for Gene Therapy, Aaron D. Miller and Edith Miller Chair for Gene Therapy and a leader in HIV research. City of Hope remains at the forefront of clinical research that changes peoples lives for the better.

When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence. I never thought I would live to see the day that I no longer have HIV. City of Hope made that possible, and I am beyond grateful. The City of Hope patient

The story above is one significant example of several important advances being made at City of Hope in the care of people with HIV. When many centers still treated patients with low-intensity, noncurative treatment approaches for HIV-related lymphoma, City of Hope challenged that paradigm by demonstrating that autologous transplantation could be used to cure patients who would otherwise die.

More recently, City of Hope is leveraging its leadership in CAR T cell therapya groundbreaking treatment currently used to rally the bodys natural defenses against cancer and exploring its potential in tandem with another advance, City of Hopes vaccine for cytomegalovirus (CMV).

In a proof-of-concept study, funded by theCalifornia Institute for Regenerative Medicine, lab models demonstrated that the combination therapy could recognize and eliminate HIV without serious toxicity to cells in the virus host. In cultured human cells, the CAR T cells killed cells tagged with the gp120 protein, and kept killing them, without significant signs of risking damage to healthy cells. In a mouse model for HIV/AIDS, high doses of the dual-action CAR T cells followed by the CMV vaccine were successful in controlling HIV, and even nestled into the bone marrow, indicating potential for treatment to keep working over the long term.

In addition to achieving breakthrough outcomes in cancer and HIV, City of Hope has been recognized as the seventh "Best Hospital" for cancer in the nation according to U.S. News & World Report's 2022-23 Best Hospitals: Specialty Ranking. This marks the first time the cancer treatment center has cracked the top 10 of the U.S. News & World Report annual rankings and the 16th consecutive year it has been distinguished as one of the nation's elite cancer hospitals. It was also rated as high performing in four cancer surgery specialties: lung, colon, prostate and ovarian cancers.

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From optimized stem cell transplants to CAR T cell therapy: Advancing options for cancer, HIV and more - City of Hope

Pluripotent embyronic cell group giving rise to diverse cell lineages

Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineageincluding melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia.[1][2]

After gastrulation, neural crest cells are specified at the border of the neural plate and the non-neural ectoderm. During neurulation, the borders of the neural plate, also known as the neural folds, converge at the dorsal midline to form the neural tube.[3] Subsequently, neural crest cells from the roof plate of the neural tube undergo an epithelial to mesenchymal transition, delaminating from the neuroepithelium and migrating through the periphery where they differentiate into varied cell types.[1] The emergence of neural crest was important in vertebrate evolution because many of its structural derivatives are defining features of the vertebrate clade.[4]

Underlying the development of neural crest is a gene regulatory network, described as a set of interacting signals, transcription factors, and downstream effector genes that confer cell characteristics such as multipotency and migratory capabilities.[5] Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiple cell lineages. Abnormalities in neural crest development cause neurocristopathies, which include conditions such as frontonasal dysplasia, WaardenburgShah syndrome, and DiGeorge syndrome.[1]

Therefore, defining the mechanisms of neural crest development may reveal key insights into vertebrate evolution and neurocristopathies.

Neural crest was first described in the chick embryo by Wilhelm His Sr. in 1868 as "the cord in between" (Zwischenstrang) because of its origin between the neural plate and non-neural ectoderm.[1] He named the tissue ganglionic crest since its final destination was each lateral side of the neural tube where it differentiated into spinal ganglia.[6] During the first half of the 20th century the majority of research on neural crest was done using amphibian embryos which was reviewed by Hrstadius (1950) in a well known monograph.[7]

Cell labeling techniques advanced the field of neural crest because they allowed researchers to visualize the migration of the tissue throughout the developing embryos. In the 1960s Weston and Chibon utilized radioisotopic labeling of the nucleus with tritiated thymidine in chick and amphibian embryo respectively. However, this method suffers from drawbacks of stability, since every time the labeled cell divides the signal is diluted. Modern cell labeling techniques such as rhodamine-lysinated dextran and the vital dye diI have also been developed to transiently mark neural crest lineages.[6]

The quail-chick marking system, devised by Nicole Le Douarin in 1969, was another instrumental technique used to track neural crest cells.[8][9] Chimeras, generated through transplantation, enabled researchers to distinguish neural crest cells of one species from the surrounding tissue of another species. With this technique, generations of scientists were able to reliably mark and study the ontogeny of neural crest cells.

A molecular cascade of events is involved in establishing the migratory and multipotent characteristics of neural crest cells. This gene regulatory network can be subdivided into the following four sub-networks described below.

First, extracellular signaling molecules, secreted from the adjacent epidermis and underlying mesoderm such as Wnts, BMPs and Fgfs separate the non-neural ectoderm (epidermis) from the neural plate during neural induction.[1][4]

Wnt signaling has been demonstrated in neural crest induction in several species through gain-of-function and loss-of-function experiments. In coherence with this observation, the promoter region of slug (a neural crest specific gene) contains a binding site for transcription factors involved in the activation of Wnt-dependent target genes, suggestive of a direct role of Wnt signaling in neural crest specification.[10]

The current role of BMP in neural crest formation is associated with the induction of the neural plate. BMP antagonists diffusing from the ectoderm generates a gradient of BMP activity. In this manner, the neural crest lineage forms from intermediate levels of BMP signaling required for the development of the neural plate (low BMP) and epidermis (high BMP).[1]

Fgf from the paraxial mesoderm has been suggested as a source of neural crest inductive signal. Researchers have demonstrated that the expression of dominate-negative Fgf receptor in ectoderm explants blocks neural crest induction when recombined with paraxial mesoderm.[11] The understanding of the role of BMP, Wnt, and Fgf pathways on neural crest specifier expression remains incomplete.

Signaling events that establish the neural plate border lead to the expression of a set of transcription factors delineated here as neural plate border specifiers. These molecules include Zic factors, Pax3/7, Dlx5, Msx1/2 which may mediate the influence of Wnts, BMPs, and Fgfs. These genes are expressed broadly at the neural plate border region and precede the expression of bona fide neural crest markers.[4]

Experimental evidence places these transcription factors upstream of neural crest specifiers. For example, in Xenopus Msx1 is necessary and sufficient for the expression of Slug, Snail, and FoxD3.[12] Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos.[13]

Following the expression of neural plate border specifiers is a collection of genes including Slug/Snail, FoxD3, Sox10, Sox9, AP-2 and c-Myc. This suite of genes, designated here as neural crest specifiers, are activated in emergent neural crest cells. At least in Xenopus, every neural crest specifier is necessary and/or sufficient for the expression of all other specifiers, demonstrating the existence of extensive cross-regulation.[4] Moreover, this model organism was instrumental in the elucidation of the role of the Hedgehog signaling pathway in the specification of the neural crest, with the transcription factor Gli2 playing a key role.[14]

Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Twist, a bHLH transcription factor, is required for mesenchyme differentiation of the pharyngeal arch structures.[15] Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells.[16]

Finally, neural crest specifiers turn on the expression of effector genes, which confer certain properties such as migration and multipotency. Two neural crest effectors, Rho GTPases and cadherins, function in delamination by regulating cell morphology and adhesive properties. Sox9 and Sox10 regulate neural crest differentiation by activating many cell-type-specific effectors including Mitf, P0, Cx32, Trp and cKit.[4]

The migration of neural crest cells involves a highly coordinated cascade of events that begins with closure of the dorsal neural tube.

After fusion of the neural fold to create the neural tube, cells originally located in the neural plate border become neural crest cells.[17] For migration to begin, neural crest cells must undergo a process called delamination that involves a full or partial epithelial-mesenchymal transition (EMT).[18] Delamination is defined as the separation of tissue into different populations, in this case neural crest cells separating from the surrounding tissue.[19] Conversely, EMT is a series of events coordinating a change from an epithelial to mesenchymal phenotype.[18] For example, delamination in chick embryos is triggered by a BMP/Wnt cascade that induces the expression of EMT promoting transcription factors such as SNAI2 and FoxD3.[19] Although all neural crest cells undergo EMT, the timing of delamination occurs at different stages in different organisms: in Xenopus laevis embryos there is a massive delamination that occurs when the neural plate is not entirely fused, whereas delamination in the chick embryo occurs during fusion of the neural fold.[19]

Prior to delamination, presumptive neural crest cells are initially anchored to neighboring cells by tight junction proteins such as occludin and cell adhesion molecules such as NCAM and N-Cadherin.[20] Dorsally expressed BMPs initiate delamination by inducing the expression of the zinc finger protein transcription factors snail, slug, and twist.[17] These factors play a direct role in inducing the epithelial-mesenchymal transition by reducing expression of occludin and N-Cadherin in addition to promoting modification of NCAMs with polysialic acid residues to decrease adhesiveness.[17][21] Neural crest cells also begin expressing proteases capable of degrading cadherins such as ADAM10[22] and secreting matrix metalloproteinases (MMPs) that degrade the overlying basal lamina of the neural tube to allow neural crest cells to escape.[20] Additionally, neural crest cells begin expressing integrins that associate with extracellular matrix proteins, including collagen, fibronectin, and laminin, during migration.[23] Once the basal lamina becomes permeable the neural crest cells can begin migrating throughout the embryo.

Neural crest cell migration occurs in a rostral to caudal direction without the need of a neuronal scaffold such as along a radial glial cell. For this reason the crest cell migration process is termed free migration. Instead of scaffolding on progenitor cells, neural crest migration is the result of repulsive guidance via EphB/EphrinB and semaphorin/neuropilin signaling, interactions with the extracellular matrix, and contact inhibition with one another.[17] While Ephrin and Eph proteins have the capacity to undergo bi-directional signaling, neural crest cell repulsion employs predominantly forward signaling to initiate a response within the receptor bearing neural crest cell.[23] Burgeoning neural crest cells express EphB, a receptor tyrosine kinase, which binds the EphrinB transmembrane ligand expressed in the caudal half of each somite. When these two domains interact it causes receptor tyrosine phosphorylation, activation of rhoGTPases, and eventual cytoskeletal rearrangements within the crest cells inducing them to repel. This phenomenon allows neural crest cells to funnel through the rostral portion of each somite.[17]

Semaphorin-neuropilin repulsive signaling works synergistically with EphB signaling to guide neural crest cells down the rostral half of somites in mice. In chick embryos, semaphorin acts in the cephalic region to guide neural crest cells through the pharyngeal arches. On top of repulsive repulsive signaling, neural crest cells express 1and 4 integrins which allows for binding and guided interaction with collagen, laminin, and fibronectin of the extracellular matrix as they travel. Additionally, crest cells have intrinsic contact inhibition with one another while freely invading tissues of different origin such as mesoderm.[17] Neural crest cells that migrate through the rostral half of somites differentiate into sensory and sympathetic neurons of the peripheral nervous system. The other main route neural crest cells take is dorsolaterally between the epidermis and the dermamyotome. Cells migrating through this path differentiate into pigment cells of the dermis. Further neural crest cell differentiation and specification into their final cell type is biased by their spatiotemporal subjection to morphogenic cues such as BMP, Wnt, FGF, Hox, and Notch.[20]

Neurocristopathies result from the abnormal specification, migration, differentiation or death of neural crest cells throughout embryonic development.[24][25] This group of diseases comprises a wide spectrum of congenital malformations affecting many newborns. Additionally, they arise because of genetic defects affecting the formation of neural crest and because of the action of Teratogens [26]

Waardenburg's syndrome is a neurocristopathy that results from defective neural crest cell migration. The condition's main characteristics include piebaldism and congenital deafness. In the case of piebaldism, the colorless skin areas are caused by a total absence of neural crest-derived pigment-producing melanocytes.[27] There are four different types of Waardenburg's syndrome, each with distinct genetic and physiological features. Types I and II are distinguished based on whether or not family members of the affected individual have dystopia canthorum.[28] Type III gives rise to upper limb abnormalities. Lastly, type IV is also known as Waardenburg-Shah syndrome, and afflicted individuals display both Waardenburg's syndrome and Hirschsprung's disease.[29] Types I and III are inherited in an autosomal dominant fashion,[27] while II and IV exhibit an autosomal recessive pattern of inheritance. Overall, Waardenburg's syndrome is rare, with an incidence of ~ 2/100,000 people in the United States. All races and sexes are equally affected.[27] There is no current cure or treatment for Waardenburg's syndrome.

Also implicated in defects related to neural crest cell development and migration is Hirschsprung's disease (HD or HSCR), characterized by a lack of innervation in regions of the intestine. This lack of innervation can lead to further physiological abnormalities like an enlarged colon (megacolon), obstruction of the bowels, or even slowed growth. In healthy development, neural crest cells migrate into the gut and form the enteric ganglia. Genes playing a role in the healthy migration of these neural crest cells to the gut include RET, GDNF, GFR, EDN3, and EDNRB. RET, a receptor tyrosine kinase (RTK), forms a complex with GDNF and GFR. EDN3 and EDNRB are then implicated in the same signaling network. When this signaling is disrupted in mice, aganglionosis, or the lack of these enteric ganglia occurs.[30]

Prenatal alcohol exposure (PAE) is among the most common causes of developmental defects.[31] Depending on the extent of the exposure and the severity of the resulting abnormalities, patients are diagnosed within a continuum of disorders broadly labeled Fetal Alcohol Spectrum Disorder (FASD). Severe FASD can impair neural crest migration, as evidenced by characteristic craniofacial abnormalities including short palpebral fissures, an elongated upper lip, and a smoothened philtrum. However, due to the promiscuous nature of ethanol binding, the mechanisms by which these abnormalities arise is still unclear. Cell culture explants of neural crest cells as well as in vivo developing zebrafish embryos exposed to ethanol show a decreased number of migratory cells and decreased distances travelled by migrating neural crest cells. The mechanisms behind these changes are not well understood, but evidence suggests PAE can increase apoptosis due to increased cytosolic calcium levels caused by IP3-mediated release of calcium from intracellular stores. It has also been proposed that the decreased viability of ethanol-exposed neural crest cells is caused by increased oxidative stress. Despite these, and other advances much remains to be discovered about how ethanol affects neural crest development. For example, it appears that ethanol differentially affects certain neural crest cells over others; that is, while craniofacial abnormalities are common in PAE, neural crest-derived pigment cells appear to be minimally affected.[32]

DiGeorge syndrome is associated with deletions or translocations of a small segment in the human chromosome 22. This deletion may disrupt rostral neural crest cell migration or development. Some defects observed are linked to the pharyngeal pouch system, which receives contribution from rostral migratory crest cells. The symptoms of DiGeorge syndrome include congenital heart defects, facial defects, and some neurological and learning disabilities. Patients with 22q11 deletions have also been reported to have higher incidence of schizophrenia and bipolar disorder.[33]

Treacher Collins Syndrome (TCS) results from the compromised development of the first and second pharyngeal arches during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. TCS is caused by the missense mutation of the TCOF1 gene, which causes neural crest cells to undergo apoptosis during embryogenesis. Although mutations of the TCOF1 gene are among the best characterized in their role in TCS, mutations in POLR1C and POLR1D genes have also been linked to the pathogenesis of TCS.[34]

Neural crest cells originating from different positions along the anterior-posterior axis develop into various tissues. These regions of neural crest can be divided into four main functional domains, which include the cranial neural crest, trunk neural crest, vagal and sacral neural crest, and cardiac neural crest.

Cranial neural crest migrates dorsolaterally to form the craniofacial mesenchyme that differentiates into various cranial ganglia and craniofacial cartilages and bones.[21] These cells enter the pharyngeal pouches and arches where they contribute to the thymus, bones of the middle ear and jaw and the odontoblasts of the tooth primordia.[35]

Trunk neural crest gives rise two populations of cells.[36] One group of cells fated to become melanocytes migrates dorsolaterally into the ectoderm towards the ventral midline. A second group of cells migrates ventrolaterally through the anterior portion of each sclerotome. The cells that stay in the sclerotome form the dorsal root ganglia, whereas those that continue more ventrally form the sympathetic ganglia, adrenal medulla, and the nerves surrounding the aorta.[35]

The vagal and sacral neural crest cells develop into the ganglia of the enteric nervous system and the parasympathetic ganglia.[35]

Cardiac neural crest develops into melanocytes, cartilage, connective tissue and neurons of some pharyngeal arches. Also, this domain gives rise to regions of the heart such as the musculo-connective tissue of the large arteries, and part of the septum, which divides the pulmonary circulation from the aorta.[35]The semilunar valves of the heart are associated with neural crest cells according to new research.[37]

Several structures that distinguish the vertebrates from other chordates are formed from the derivatives of neural crest cells. In their "New head" theory, Gans and Northcut argue that the presence of neural crest was the basis for vertebrate specific features, such as sensory ganglia and cranial skeleton. Furthermore, the appearance of these features was pivotal in vertebrate evolution because it enabled a predatory lifestyle.[38][39]

However, considering the neural crest a vertebrate innovation does not mean that it arose de novo. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by the co-option of new upstream regulators or by the employment of new downstream gene targets, thus placing existing networks in a novel context.[40][41] This idea is supported by in situ hybridization data that shows the conservation of the neural plate border specifiers in protochordates, which suggest that part of the neural crest precursor network was present in a common ancestor to the chordates.[5] In some non-vertebrate chordates such as tunicates a lineage of cells (melanocytes) has been identified, which are similar to neural crest cells in vertebrates. This implies that a rudimentary neural crest existed in a common ancestor of vertebrates and tunicates.[42]

Ectomesenchyme (also known as mesectoderm):[43] odontoblasts, dental papillae, the chondrocranium (nasal capsule, Meckel's cartilage, scleral ossicles, quadrate, articular, hyoid and columella), tracheal and laryngeal cartilage, the dermatocranium (membranous bones), dorsal fins and the turtle plastron (lower vertebrates), pericytes and smooth muscle of branchial arteries and veins, tendons of ocular and masticatory muscles, connective tissue of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid) dermis and adipose tissue of calvaria, ventral neck and face

Endocrine cells:chromaffin cells of the adrenal medulla, glomus cells type I/II.

Peripheral nervous system:Sensory neurons and glia of the dorsal root ganglia, cephalic ganglia (VII and in part, V, IX, and X), Rohon-Beard cells, some Merkel cells in the whisker,[44][45] Satellite glial cells of all autonomic and sensory ganglia, Schwann cells of all peripheral nerves.

Enteric cells:Enterochromaffin cells.[46]

Melanocytes and iris muscle and pigment cells, and even associated with some tumors (such as melanotic neuroectodermal tumor of infancy).

Originally posted here:
Neural crest - Wikipedia

Jeanne Loring likes to say shes been to space without her feet even leaving the ground.

Just weeks ago, the Scripps Research Institute professor of molecular medicine sent some of her own genetically mapped cells to space as part of first-of-its-kind research to study the progression and onset of Parkinsons disease, multiple sclerosis and other neurodegenerative diseases.

I love traveling. Ive been on all the continents, and so I figured, whats left? Loring said jokingly. I just jumped at the opportunity when I learned that it was possible.

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In July, the cells arrived via cargo spacecraft at the International Space Station, where they remained under close observation for about a month 250 miles above Earth, and traveling at 17,500 miles per hour before they splashed back down to Earth last week.

The study is part of new National Stem Cell Foundation-funded neurodegeneration research to observe how cells communicate in microgravity in a way not possible on Earth, explained Paula Grisanti, founder and CEO of the foundation.

Its really pure exploration at this point, because theres no history of anybody doing this before, she said. Were paving the path.

An organoid derived from Dr. Jeanne Lorings induced pluripotent stem cells is prepared to be sent to the International Space Station.

(Courtesy of Dr. Davide Marotta)

Loring, a Del Mar resident who is one of the worlds leading experts in Parkinsons and a senior scientific advisor for the foundation, has been working with human-induced pluripotent stem cells since the technology was first discovered in 2006.

Called organoids, these cells are made from human skin tissue, which is put into a culture dish and turned into pluripotent stem cells, Loring explained.

Pluripotent stem cells only exist in culture dishes, they dont exist in our bodies, she said. Pluripotent means they can form any cell type in the body so for Loring, that meant forming nerve cells to create brain-like structures.

Its hard to study peoples brains, Loring said. You can do all this external stuff like they do with physical exams, but theres not any window into the brain so this is providing a sort of brain avatar.

Organoids provide a stand-in for the brain that can be studied by researchers, Loring explained. They make connections with each other, the cells talk to each other, so in a lot of ways, its a really good model of the brain, she added.

Moreover, the organoids mimic the brains of people with MS and Parkinsons.

Loring has been working with these organoids for years through Aspen Neuroscience, a San Diego-based company she co-founded that is working to create the worlds first personalized cell therapy for Parkinsons, using a patients own cells so they dont have to worry about rejection. Clinical trials may start as early as next year, she said.

Tubes containing neural organoids are loaded into a rack in preparation for placement in Cube Lab to travel to the International Space Station.

(Courtesy of Space Tango)

For the last four years, the foundations team of bicoastal researchers has been working together to study these organoids in space.

While an experiment in space presents its own challenges, Loring said its worth the work, as researchers hope to gain valuable and unique insight into how disorders like Parkinsons and MS develop. You can see them interacting and talking to each other in 3-D in a way that you cannot on Earth, Grisanti said.

Along with Lorings healthy organoids, which are used as a control, organoids derived from patients with Parkinsons and MS were sent to the space station, while the entire experiment was replicated on Earth.

Specifically, researchers are studying the neuroinflammation in the organoids, which is like when the immune system in the brain is overactive, Grisanti explained.

Organoid cultures are sealed in holders and ready to be placed in Cube Lab for space flight. The cover shows National Stem Cell Foundations SpaceX CRS-25 mission patch.

(Courtesy of Space Tango)

What we hope to find is a point at which things start to go wrong in those neurodegenerative diseases, where we could then intervene with a new drug or cell therapy, she said. And were seeing signs that that happens more in space than it does on the ground, so it helps create the type of interaction that you would see early in a neurodegenerative disease.

Grisanti said they hope to be able to use this research to develop a new drug or cell therapy to treat these disorders and potentially other neurodegenerative diseases in the future.

I think weve cracked the door open, but weve got some more flying to do, she added.

Continued here:
To better understand Parkinson's disease, this San Diego expert sent her own cells to space - The San Diego Union-Tribune

Westford, USA, Aug. 25, 2022 (GLOBE NEWSWIRE) -- As the world increasingly becomes connected and people live longer, surgery and medical procedures become more complex. Surgery, one of the most common medical procedures, is now estimated to use over 1 million surgical tools each year. In order to meet the rising demand for surgical tools, surgeons are turning to biomaterials as a key component in their procedures. The main reason for this growth of the global biomaterials market is the increasing demand for novel biomaterials in various sectors such as automotive, aerospace, construction, and medical applications.

The growing demand for biomaterials has led to several companies developing unique biomaterials specifically for surgery. Some of the most well-known biomedical materials including polypropylene microspheres, chitosan hydrogel, and alginate matrix were pioneers in the field of biomaterials. Today, there are numerous new types of biomaterials being developed and marketed for a variety of medical applications, such as wound healing and orthopedic surgery. Global biomaterials market is expanding rapidly due to increasing public awareness of the benefits of using these materials and growing demand from pharmaceutical and medical device companies.

SkyQuest has published a report on global biomaterials market. The report provides a detailed market analysis, which would help the market participant in gaining is insights about market forecast, company profiles, market share, pricing analysis, competitive landscape, value chain analysis, porters five, and pestle among others.

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Demand For Biomaterials in the Healthcare Industry will Grow by 53% Over the Next Five Years

The demand for biomaterials market in the healthcare industry is growing rapidly, according to SkyQuest study. We studied global economic data and discovered that the demand for biomaterials in the healthcare industry will grow by 53% over the next five years. In 2021, 10.7 million patients used some kind of biomaterials across different applications such as wound care, tissue implant, surgeries, and medical devices, among others. This rising demand is impacting not only hospitals and clinics, but also diagnostic laboratories and pharmaceutical companies.

Most biomedical materials are manufactured from organic materials such as skin, bone, cartilage, and tendons. While these materials can be derived from a variety of sources, synthetic biomedical materials are often cheaper and more readily available. However, synthetic biomedical materials do not have the same properties as natural materials, which means they may not be as effective when used in medical treatments. Biologically based biomaterials are more effective because they can mimic the properties of natural tissues. Their potential benefits make them a highly desired commodity in the healthcare industry across the global biomaterials market. In 2021 alone, sales of artificial joints were worth $2.2 billion, while sales of regenerative medicine products such as stem cells and platelet-rich plasma were estimated to be worth $8.8 billion in the same year.

SkyQuest has done a detailed study on global biomaterials market and prepared a report that also covers current consumer base, potential demand for products, demand analysis by category and volume, expected growth, prominent growth factors, market dynamics, trends, opportunities, and innovation, among others.

Browse summary of the report and Complete Table of Contents (ToC):

https://skyquestt.com/report/biomaterials-market

Top 4 Biomaterials in Global Market

1. Stem cells- Stem cells have become one of the most promising areas of biomaterial research because they can be modified to create a wide variety of tissue types, including cartilage, skin, and bone.

2. Chitosan- Chitosan is a natural polymer found in creatures ranging from crabs to shrimp, and it is prized for its ability to form strong and durable bonds with other materials.

3. Polycaprolactone- Polycaprolactone is a modified form cellulose that has been shown to have many potential biomedical applications, including as a replacement for hard tissues like heart valves and bones.

4. Mesenchymal stem cells- Mesenchymal stem cells (MSCs) are adult cells found in the connective tissue and skeletal muscles of mammals. MSCs have characteristics that make them especially effective at repairing tissues damaged by disease or injury, which is why they are commonly used in studies on regenerative therapies.

Recent Advancements in Biomaterials Market

Successful applications of biomaterials in disease treatment have made them a preferred choice for many medical procedures. For example, use of biomaterials for artificial heart valves has revolutionized the way these devices are operated and prevented heart failure in patients.

In addition, various biomaterials are being developed for use in regenerative medicine. For example, researchers in the global biomaterials market are exploring the possibilities of using nano-sized polymers to promote the growth of new tissue in injured or damaged tissues. This approach may prove to be an effective way to restore function to damaged organs and limbs.

Biomaterials are also being used to create new types of prosthetic devices. For example, doctors are currently testing a new type of artificial hip that uses a biocompatible material as its main component.

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SkyQuests report on global biomaterials market would help you in gaining insights about current developments and its impact on the overall market growth, pricing, demand and supply, change in growth strategies of existing players, among others. Also, the report would help in understanding how the market value is changing and affecting the forecast revenue over the period.

Top Players in the Global Biomaterials Market

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Global Cell Therapy Market

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Global Biopharmaceutical Analytical Testing Services Market

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Global Biomaterials Market to Reach Value of $372.7 Billion by 2028 | Demand For Biomaterials in the Healthcare Industry will Grow by 53% Over the...

SOMERVILLE, Mass., Aug. 25, 2022 (GLOBE NEWSWIRE) -- Finch Therapeutics Group, Inc. (“Finch” or “Finch Therapeutics”) (Nasdaq: FNCH), a clinical-stage microbiome therapeutics company leveraging its Human-First Discovery® platform to develop a novel class of orally administered biological drugs, today announced that it will regain full development and commercial rights to FIN-524 (previously known as TAK-524) and FIN-525 from Takeda Pharmaceutical Company Limited (“Takeda”). Following a review of its pipeline, Takeda informed Finch of its decision to terminate its collaboration with Finch, effective November 17, 2022, resulting in the return to Finch of worldwide rights to develop and commercialize FIN-524, FIN-525, and any other microbiome product candidates for inflammatory bowel disease (IBD). FIN-524 and FIN-525 are investigational, orally administered targeted microbiome product candidates composed of bacterial strains selected for their potential immuno-modulatory properties.

Continued here:
Finch Therapeutics Regains Full Rights to FIN-524 and FIN-525 Targeted Microbiome Product Candidates in Development for IBD

What Are Hematopoietic Stem Cells and Why Are They Important? Hematopietic stem cells (HSCs) are multipotent cells found in the blood and bone marrow with the ability to self-renew and differentiate into multiple cell types during bone marrow hematopoiesis. Clinicians use HSCs to replace or repopulate a patients blood as a form of regenerative medicine. Research into HSC development and aging facilitates better in vitro HSC expansion and broadens their potential for disease treatment, enhancing their clinical therapeutic effects.

How Hematopoietic Stem Cells DevelopHSCs begin their development during embryogenesis in the dorsal aortic tissue and are additionally found in the placenta, yolk sac, and fetal liver. This fetal hematopoiesis process is necessary to produce the blood cells required for tissue development while generating a pool of undifferentiated HSCs. At birth, these HSCs migrate into and populate the newly-formed bone marrow and maintain a steady state of self-renewal and differentiation.1 HSCs function by producing red blood cells, platelets, and white blood cells throughout life, maintaining their levels following bleeding and infection. HSCs generally give rise to partly differentiated but proliferative progenitors, which differentiate into mature cells. Because of this process, true HSCs are relatively rare in the human body.2

Using Hematopoietic Stem Cells for Research and TreatmentHematopoietic stem cell transplantsFor more than 60 years, hematopoietic stem cell transplants (HSCTs) have been the most common form of HSC therapy, and are a standard option for treating hematologic malignancies, immunodeficiency, and defective hematopoiesis disorders. HSCs are now derived from multiple sources, such as peripheral and cord blood and bone marrow. Before transplantation, the receiving patient must undergo severe immunosuppressive procedures to prevent rejection of the new stem cells.3

Hematopoietic stem cell isolationThe most common HSC isolation method involves removing blood cells from plasma using density gradient centrifugation followed by magnetic bead isolation using the CD34+ surface marker, a general marker for all hematopoietic progenitors. Using flow cytometry, scientists sort specific HSC cell types based on common cell surface markers.4 Clinicians then intravenously infuse these cells into the receiver patients marrow where they engraft and repopulate the blood and immune system. In blood cancers such as leukemias and lymphomas, restoration of the blood system by HSCT allows patients to receive high-dose chemotherapy treatments, ridding them of malignant cells. In patients with red blood cell conditions where continuous blood transfusions are not an option, such as thalassemia major, HSCT results in 80 percent disease-free survival.5

Hematopoietic stem cells in gene and tissue regeneration therapyBone marrow hematopoietic stem cells also differentiate into cells of other lineages, such as endothelial cells, cardiomyocytes, neural cells, and hepatocytes, in a process called transdifferentiation. Because adult stem cells are rare, understanding the mechanisms behind HSC transdifferentiation could provide an additional source of tissue-specific multipotent cells and influence future clinical methods for tissue regeneration. HSCs can also help repair injured organs by releasing regenerative cytokines and recruiting cells to the damage site.5 Some of the latest advances in HSC therapeutic research involve using methods such as CRISPR for correcting genetically-defective HSCs. These methods will allow a patient to receive their own genetically-compatible (syngeneic) HSCs. These are called allogeneic transplants and are more effective at avoiding graft-versus-host disease, a condition where transplants from a donor are rejected by the recipients body, leading to an immune response against other tissues and organs. Creating genetically-corrected induced pluripotent stem cells (iPSCs) from patient skin tissues and differentiating them into HSCs has also been an active area of research, although current methods remain costly and time-consuming.6 Further research is necessary to take advantage of these remarkable multipotent cells in disease therapies.

References

1. H.K. Mikkola, S.H. Orkin, The journey of developing hematopoietic stem cells, Development, 133(19):3733-44, 2006.

2. G.M. Crane et al., Adult haematopoietic stem cell niches, Nat Rev Immunol, 17(9):573-90, 2017.

3. S. Giralt, M.R. Bishop, Principles and overview of allogeneic hematopoietic stem cell transplantation, Cancer Treat Res, 144:1-21, 2009.

4. B. Kumar, S.S. Madabushi, Identification and isolation of mice and human hematopoietic stem cells, Methods Mol Biol, 1842:55-68, 2018.

5. J.Y. Lee, S.H. Hong, Hematopoietic stem cells and their roles in tissue regeneration, Int J Stem Cells, 13(1):1-12, 2020.

6. S. Demirci et al., Hematopoietic stem cells from pluripotent stem cells: Clinical potential, challenges, and future perspectives, Stem Cells Transl Med, 9(12):1549-57, 2020.

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Brush Up: Hematopoietic Stem Cells and Their Role in Development and Disease Therapy - The Scientist

According to the National Cancer Institute, over 60,000 people will be diagnosed with leukemia this year and 24.000 will die. The NCI explains, "There is no standard staging system for leukemia. The disease is described as untreated, in remission, or recurrent," and while there's no way to prevent the cancer, there are lifestyle choices like not smoking that help reduce the risk. Read on to learn what experts say about leukemia and to ensure your health and the health of others, don't miss these Sure Signs You've Already Had COVID.

The Mayo Clinic says, "Leukemia is cancer of the body's blood-forming tissues, including the bone marrow and the lymphatic system. Many types of leukemia exist. Some forms of leukemia are more common in children. Other forms of leukemia occur mostly in adults. Leukemia usually involves the white blood cells. Your white blood cells are potent infection fighters they normally grow and divide in an orderly way, as your body needs them. But in people with leukemia, the bone marrow produces an excessive amount of abnormal white blood cells, which don't function properly."

The National Cancer Institute says, "Leukemia is cancer that starts in the tissue that forms blood. Most blood cells develop from cells in the bone marrow called stem cells. In a person with leukemia, the bone marrow makes abnormal white blood cells. The abnormal cells are leukemia cells. Unlike normal blood cells, leukemia cells don't die when they should. They may crowd out normal white blood cells, red blood cells, and platelets. This makes it hard for normal blood cells to do their work. The four main types of leukemia are:6254a4d1642c605c54bf1cab17d50f1e

Acute lymphoblastic leukemia (ALL)

Acute myelogenous leukemia (AML)

Chronic lymphocytic leukemia (CLL)

Chronic myelogenous leukemia (CML)"

The Cleveland Clinic explains, "Leukemia is often considered a childhood illness. Even though it is one of the most common childhood cancers, the blood disorder cancer actually affects far more adults. According to the National Cancer Institute, leukemia is most frequently diagnosed among people between the ages of 65 and 74 years. The median age at diagnosis is 66. There are treatment options for patients of all ages, include chemotherapy and blood transfusions."

According to the Mayo Clinic, "Leukemia symptoms vary, depending on the type of leukemia. Common leukemia signs and symptoms include:

The Mayo Clinic states, "Factors that may increase your risk of developing some types of leukemia include:

Heather Newgen

Continued here:
Sure Signs You Have Leukemia, Say Physicians Eat This Not That - Eat This, Not That

MONDAY, Aug. 22, 2022 (HealthDay News) -- The COVID-19 pandemic was associated with a decrease in transplantation in 2020, according to a study published in the July 1 issue of the American Journal of Surgery.

Alejandro Suarez-Pierre, M.D., from the University of Colorado School of Medicine in Aurora, and colleagues examined adult transplantation data as time series data in a population-based cohort study. Models of transplantation rates were developed using data from 1990 to 2019 to project the expected 2020 rates in a theoretical scenario in which the pandemic did not occur. Observed-to-expected (O/E) ratios were calculated for transplants.

The researchers found that 32,594 transplants were expected in 2020, but 30,566 occurred (O/E, 0.94; 95 percent confidence interval, 0.88 to 0.99). A total of 50,241 waitlist registrations occurred compared with 58,152 expected (O/E, 0.86; 95 percent confidence interval, 0.80 to 0.94). For kidney, liver, heart, and lung, the O/E ratios (95 percent confidence intervals) of transplants were 0.92 (0.86 to 0.98), 0.96 (0.89 to 1.04), 1.05 (0.91 to 1.23), and 0.92 (0.82 to 1.04), respectively. The corresponding O/E ratios (95 percent confidence intervals) of waitlist registrations were 0.84 (0.77 to 0.93), 0.95 (0.86 to 1.06), 0.99 (0.85 to 1.18), and 0.80 (0.70 to 0.94).

"The COVID-19 pandemic was associated with a significant deficit in solid organ transplantation, donation, and waitlist registrations in the United States in 2020. The impact was strongest in kidney transplantation and waitlist registration," the authors write. "While the pandemic persisted through 2020, the transplant system adapted remarkably well with a record number of transplantations performed."

Abstract/Full Text

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Drop Seen in Transplantation in 2020 With COVID-19 Pandemic - Consumer Health News | HealthDay - HealthDay News

The therapeutic efficacy of intravenous hiPSC-MSCs infusion without intramuscular cellular transplantation

First, we determined whether hiPSC-MSCs could migrate into the ischemic limb after a single intravenous cellular infusion. Our results showed that most of the hiPSC-MSCs engrafted into the liver 12h after infusion (Supplementary Fig.1). The engrafted hiPSC-MSCs gradually migrated into the ischemic limb at day 3 and disappeared at day 14 (Supplementary Fig.1). A few cells engrafted in the ischemic limb, the engraftment rate was extremely low, evidenced by the DiR signal that was 9.8106 at day 7 after a single intravenous administration of 5105 hiPSC-MSCs versus 1.4109 7 days after a single intramuscular injection.

To compare intravenous cellular administration and intramuscular cellular delivery, three groups of mice that received intravenous hiPSC-MSC infusion once, every week or every 3 days without intramuscular administration of hiPSC-MSCs respectively and one group that received intramuscular hiPSC-MSC delivery only were employed (Fig.1a). Intravenous administration of hiPSC-MSCs once, every week or every 3 days without intramuscular administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week and Saline-MSC/3 days groups significantly improved blood perfusion from day 7 onwards compared with the ischemia group (Fig.1b, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the Saline-MSC/week and Saline-MSC/3 days groups further increased blood perfusion at day 35 compared with the Saline-MSC/once group (Fig.1b, all p<0.05), although there was no difference between the first two groups (Fig.1b, p>0.05). Nevertheless intramuscular administration of hiPSC-MSCs in the MSC-Saline group achieved a better beneficial effect than intravenous administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week and Saline-MSC/3 days groups from day 21 onwards (Fig.1b, all p<0.05).

To evaluate blood perfusion in the groups that received intravenous hiPSC-MSCs infusion without intramuscular hiPSC-MSCs transplantation, Laser Doppler imaging analysis was performed immediately and every week following femoral artery ligation (a). A single or repeated intravenous administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week or Saline-MSC/3 days groups significantly increased blood perfusion from day 7 onwards compared with the ischemia group. Moreover, repeated intravenous hiPSC-MSCs infusion further improved blood perfusion at day 35. Nonetheless intramuscular hiPSC-MSC transplantation in the MSC-Saline group showed a superior beneficial effect over repeated intravenous hiPSC-MSC infusion in the Saline-MSC/week and Saline-MSC/3 days groups (b).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs without intramuscular administration of hiPSC-MSCs improved blood perfusion. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days without intramuscular administration of hiPSC-MSCs further increased blood perfusion compared with a single intravenous injection, although there was no significant difference between intravenous administration repeated every week versus every 3 days. Nonetheless intramuscular administration of hiPSC-MSCs achieved a better beneficial effect than intravenous administration of hiPSC-MSCs once, every week or every 3 days.

Five groups of ICR mice were employed in the main experiment (Fig.2): (1) ischemia group receiving intravenous administration of saline immediately after induction of ischemia and intramuscular administration of culture medium at day 7; (2) MSC-Saline group receiving intravenous administration of saline immediately after induction of ischemia and intramuscular administration of 3106 hiPSC-MSCs at day 7; (3) MSC-MSC/once group receiving intravenous administration of 5105 hiPSC-MSCs immediately after induction of ischemia and intramuscular administration of 3106 hiPSC-MSCs at day 7; (4) MSC-MSC/week group receiving repeated intravenous administration of 5105 hiPSC-MSCs immediately and every week following induction of ischemia for 4 weeks and intramuscular administration of 3106 hiPSC-MSCs at day 7; (5) MSC-MSC/3 days group receiving repeated intravenous administration of 5105 hiPSC-MSCs immediately and every 3 days following induction of ischemia for 4 weeks and intramuscular administration of 3106 hiPSC-MSCs at day 7.

There are five groups of ICR mice in main experiment: ischemia group, MSC-Saline group, MSC-MSC/once group, MSC-MSC/week group, MSC-MSC/3 days group.

Serial laser doppler imaging and analysis was performed to evaluate the blood perfusion and monitor the blood flow recovery in the ischemic hind limb (Fig.3a). After induction of ischemia, blood perfusion of the ligated limb significantly decreased to an extremely low level relative to the non-ligated limb in the ischemia group (2.980.56), MSC-Saline group (2.960.30), MSC-MSC/once group (2.950.48), MSC-MSC/week group (3.010.29) and MSC-MSC/3 days group (2.970.30). There was no significant difference between the five groups (Fig.3b, all p>0.05). These results confirmed that acute hind-limb ischemia was induced in all groups. Intramuscular administration of hiPSC-MSCs with intravenous administration of saline or with intravenous administration of hiPSC-MSCs once or every week or every 3 days in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups resulted in a significant and progressive improvement in the blood perfusion of the ligated limb from day 14 onwards compared with the ischemia group (Fig.3b, all p<0.05). Intravenous administration of hiPSC-MSCs significantly increased blood perfusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.3b, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further increased blood perfusion from day 28 onwards compared with the MSC-MSC/once group (Fig.3b, all p<0.05). Nevertheless there was no significant difference between mice that received repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week versus MSC-MSC/3 days groups throughout the study period. On day 35, blood perfusion of the ligated hind limb in the ischemia, MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups were 30.570.81, 40.560.84, 44.990.75, 50.410.68 and 51.120.86 respectively.

Laser Doppler imaging analysis was performed immediately and every week following femoral artery ligation to evaluate blood perfusion in the ischemic hind limbs (a). After intramuscular transplantation of hiPSC-MSCs, blood perfusion was significantly improved in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group from day 14 onwards (all p<0.05). A single and repeated intravenous hiPSC-MSC infusion further improved blood perfusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with MSC-Saline group (all p<0.05). Moreover, the blood perfusion was significantly higher in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (all p<0.05). There was no significant difference between the MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Taken together, our results showed that systemic intravenous administration of hiPSC-MSCs combined with intramuscular transplantation of hiPSC-MSCs improved blood perfusion in a mouse model of hind-limb ischemia relative to intramuscular hiPSC-MSC transplantation without systemic hiPSC-MSC delivery. In addition, repeated intravenous administration of hiPSC-MSCs every week or every 3 days further improved the therapeutic effects of hiPSC-MSC-based therapy compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

To evaluate neovascularization in the ischemic limb, immunohistochemical staining with anti-mouse alpha-smooth muscle antigen (-SMA) and anti-mouse von Willebrand factor (vWF) antibodies were performed to assess arteriogenesis and angiogenesis following cellular transplantation respectively (Fig.4a). On day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not increase arteriogenesis and capillary formation (Fig.4b,c, p>0.05). Nevertheless, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved arteriogenesis and capillary formation compared with the ischemia group (Fig.4b,c, all p<0.05). On day 35, compared with the ischemia group, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased neovascularization (Fig.4b,c, all p<0.05). Moreover, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups further improved neovascularization compared with the MSC-Saline group on day 35 (Fig.4b,c, p<0.05). In addition, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further promoted neovascularization compared with the MSC-MSC/once group (Fig.4b,c, all p<0.05). There was no difference in neovascularization between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.4b,c, all p>0.05).

Immunohistochemical staining with anti-mouse vWF (green) and anti-mouse -SMA (red) antibodies was performed to assess angiogenesis and arteriogenesis in ischemic tissues. Massons trichrome staining was performed to evaluate the degree of fibrosis (a). On day 14, neovascularization was markedly increased in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, not in the MSC-Saline group, relative to the ischemia group. On day 35, after intramuscular transplantation of hiPSC-MSCs, neovascularization was significantly improved in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). Intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups enhanced the therapeutic effects of intramuscularly transplanted hiPSC-MSCs on neovascularization compared with the MSC-Saline group (all p<0.05). Moreover, neovascularization was further enhanced by repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (b, c). On day 14, fibrosis was remarkably decreased in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, not in the MSC-Saline group, relative to the ischemia group. On day 35, after intramuscular transplantation of hiPSC-MSCs, fibrosis was significantly reduced in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). Intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups enhanced the therapeutic effects of intramuscularly transplanted hiPSC-MSCs on reduction of fibrosis compared with the MSC-Saline group (all p<0.05). Moreover, the anti-fibrotic effect was further enhanced by repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (d).

To assess the degree of fibrosis in the ischemic limb, Massons Trichrome staining were performed to determine the percentage of fibrotic tissue in the ischemic limb (Fig.4a). On day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not decrease fibrosis (Fig.4d, p>0.05). Nevertheless, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced fibrosis compared with the ischemia group (Fig.4d, all p<0.05). Compared with the ischemia group, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly ameliorated fibrosis on day 35 (Fig.4d, all p<0.05). Moreover, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced fibrosis compared with the MSC-Saline group (Fig.4d, all p<0.05). In addition, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further decreased fibrosis compared with the MSC-MSC/once group (Fig.4d, all p<0.05). There were no differences in fibrosis between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.4d, all p>0.05).

Taken together, our results showed that systemic intravenous administration of hiPSC-MSCs combined with intramuscular transplantation of hiPSC-MSCs promoted neovascularization and reduced fibrosis in a mouse model of hind-limb ischemia. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further increased the neovascularization and decreased the fibrosis following cellular transplantation compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

Fluorescent imaging of ischemic hind limbs was performed immediately and every week after induction of ischemia to access the cellular engraftment and survival of intramuscularly transplanted hiPSC-MSCs (Fig.5a). To avoid any confusion on the fluorescent signal, intravenous administered hiPSC-MSCs were not labeled with DiR. There was no significant difference in fluorescent signal intensity over the ischemic hind limb after intramuscular cellular transplantation (Fig.5b, all p>0.05). Systemic intravenous administration of hiPSC-MSCs significantly increased cellular engraftment and survival in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards relative to the MSC-Saline group (Fig.5b, all p<0.05). Moreover, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further improved cellular engraftment and survival from day 21 onwards compared with the MSC-MSC/once group (Fig.5b, all p<0.05). There was no significant difference between mice that received repeated intravenous administration of hiPSC-MSCs in the MSC/week and MSC-MSC/3 days groups throughout the study period. On day 35, the estimated survival rates in MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups decreased to 2.590.31%, 8.330.54%, 13.560.49% and 14.230.42%, respectively (Supplementary Fig.2 and Supplementary Data1).

A series of fluorescent images of ischemic hind limbs was performed immediately and every week following intramuscular transplantation of hiPSC-MSCs to detect the fate of intramuscularly transplanted hiPSC-MSCs (a). A single or repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly prolonged the survival of intramuscular transplanted hiPSC-MSCs from day 14 onwards compared with the MSC-Saline group (all p<0.05). Moreover, repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further improved the survival of intramuscularly transplanted hiPSC-MSCs from day 21 onwards compared with the MSC-MSC/once group (all p<0.05), whereas no significant difference was observed between MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Cellular engraftment and survival of intramuscularly transplanted hiPSC-MSCs were further confirmed by immunohistochemical double staining with anti-human GAPDH and anti-human mitochondria antibodies (Fig.6a). Systemic intravenous administration of hiPSC-MSCs significantly increased human GAPDH and human mitochondria positive cells over the ischemic hind limb in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards relative to the MSC-Saline group (Fig.6b, all p<0.05). Moreover, on day 35, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further increased the human GAPDH and human mitochondria positive cells compared with the MSC-MSC/once group (Fig.6b, all p<0.05). No difference between the MSC-MSC/week and MSC-MSC/3 days groups was noted (Fig.6b, all p>0.05).

The engraftment of intramuscularly transplanted hiPSC-MSCs was further confirmed by double immunohistochemical staining with anti-human GAPDH (green) and anti-human mitochondria antibodies (red) at day 14 and 35 (a). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved the engraftment of intramuscularly transplanted hiPSC-MSCs from day 14 onwards (all p<0.05). Repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further improved the engraftment of intramuscular transplanted hiPSC-MSCs at day 35 compared with the MSC-MSC/once group (all p<0.05), whereas no significant difference was observed between the MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs enhanced engraftment and survival of intramuscularly transplanted hiPSC-MSCs. In addition, repeated intravenous administration every week or every 3 days further increased the cellular engraftment and survival compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week versus every 3 days.

Immunohistochemical staining with anti-mouse CD68 antibody was performed to calculate the number of macrophages after cellular transplantation and evaluate the infiltration of macrophages (Fig.7a). M2 macrophages were further characterized by immunohistochemical staining with anti-mouse Arginase-1 antibody (Fig.7a). Although there was no significant difference between any of the five groups at day 7 and 14 after induction of ischemia (Fig.7b, all p>0.05), intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased M2 macrophage polarization in the ligated limb from day 14 onwards relative to the ischemia group (Fig.7c, all p<0.05). Moreover, intravenous administration of hiPSC-MSCs remarkedly promoted M2 macrophage polarization in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.7c, all p<0.05). On day 35, intramuscular administration of hiPSC-MSCs in MSC-Saline group had significantly decreased the infiltration of macrophages although the M2 macrophage percentage was similar to that in the ischemia group (Fig.7b,c, all p<0.05). Systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased macrophage infiltration and increased M2 macrophage polarization relative to the MSC-Saline group (Fig.7b,c, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further reduced the infiltration of macrophages and increased the polarization of M2 macrophages compared with the MSC-MSC/once group (Fig.7b,c, all p<0.05). There was no noticeable difference in either the infiltration of macrophages or polarization of M2 macrophages between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.7b,c, all p>0.05).

Muscular infiltration of macrophages was determined by immunohistochemical staining with anti-mouse CD68 antibody (green) at day 7, 14, and 35. Number of M2 macrophages was detected by immunohistochemical staining with anti-mouse Arginase-1 antibodies (red) (a). At day 35, after intramuscular transplantation of hiPSC-MSCs, total macrophages were significantly decreased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased the muscular infiltration of macrophages compared with the MSC-Saline group (all p<0.05). In addition, repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased the muscular infiltration of macrophages compared with the MSC-MSC/once group (all p<0.05). Nevertheless no significant difference was observed between groups at day 7 and 14 (all p>0.05) (b). Intramuscular transplantation of hiPSC-MSCs without intravenous hiPSC-MSC infusion significantly increased the polarization of M2 macrophages at day 14 compared with the ischemia group (p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved the polarization of M2 macrophages from day 7 onwards (all p<0.05). Repeated hiPSC-MSCs infusion further promoted the polarization of M2 macrophages compared with a single intravenous hiPSC-MSCs infusion in the MSC-MSC/once group at day 35 (all p<0.05) (c).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs decreased the infiltration of macrophages and increased the polarization of M2 macrophages. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further decreased the infiltration of macrophages and increased the polarization of M2 macrophages compared with a single intravenous injection, whereas no significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

The limb tissue level of a specific subset-related cytokines was measured using a commercial mouse inflammatory factor array. For anti-inflammatory cytokines, on day 14, there was no significant difference on interleukin (IL)10 and vascular endothelial growth factor (VEGF) among the ischemia, MSC-Saline and MSC-MSC/once groups (Supplementary Fig.3a,b, all p>0.05). Nonetheless, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups significantly increased IL-10 and VEGF compared with the ischemia group (Supplementary Fig.3a,b, all p<0.05). Moreover, an increase of IL-10 was observed in the MSC-MSC/week and MSC-MSC/3 days groups relative to the MSC-Saline group (Supplementary Fig.3a,b, all p<0.05). On day 35, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not significantly improved IL-10 relative to ischemia group. Nevertheless, systemic intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved IL-10 compared with the ischemia group (Supplementary Fig.3a, all p<0.05). Moreover, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased IL-10 compared with the MSC-MSC/once group (Supplementary Fig.3a, all p<0.05). No significant difference on VEGF was observed among all five groups on day 35 (Supplementary Fig.3b, all p<0.05).

For inflammatory cytokines, on day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased IL-1A and IL-17A compared with the ischemia group (Supplementary Fig.3c,d, all p<0.05). Nonetheless, there was no significant difference among the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups (Supplementary Fig.3c,d, all p>0.05). There was no significant difference on IL-2 and macrophage colony-stimulating factor (MCSF) among the ischemia, MSC-Saline and MSC-MSC/once groups (Supplementary Fig.3e,f, all p>0.05). Nonetheless, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups significantly decreased IL-2 and MCSF compared with the ischemia group (Supplementary Fig.3e,f, all p<0.05). On day 35, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced IL-17A relative to ischemia group (Supplementary Fig.3d, all p<0.05). Moreover, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased IL-17A compared with the MSC-Saline and MSC-MSC/once groups respectively (Supplementary Fig.3d, all p<0.05). No significant difference on IL-1A, IL-2 and MCSF was observed among all five groups on day 35 (Supplementary Fig.3c,e,f, all p>0.05).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs could improve anti-inflammatory cytokines and decreased inflammatory cytokines. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further improved anti-inflammatory cytokines and decreased inflammatory cytokines compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

Flow cytometry analysis of fresh splenocytes was performed to assess splenic Tregs and natural killer (NK) cells populations and so determine the in vivo immunomodulatory effect of systemic administration of hiPSC-MSCs (Fig.8a). Splenic NK cells were defined as both a CD49b-FITC and NK1.1-APC positive cell population. Our result showed that splenic NK cells progressively decreased following intramuscular hiPSC-MSC transplantation or intravenous hiPSC-MSC infusion in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, whereas no significant difference was noted between different time points in the ischemia group (Supplementary Fig.4a). Compared with the ischemia group, intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased splenic NK cells from day 14 onwards (Fig.8b, all p<0.05). Systemic intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced splenic NK cells from day 7 onwards relative to the ischemia and MSC-Saline groups (Fig.8b, all p<0.05). Repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further reduced splenic NK cells from day 14 onwards compared with the MSC-MSC/once group (Fig.8b, all p<0.05). Nonetheless no significant difference was observed between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.8b, all p>0.05).

Splenic Tregs and NK cells were determined by flow cytometry analysis at day 7, 14 and 35 (a). After intramuscular transplantation of hiPSC-MSCs, splenic NK cells were significantly decreased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased splenic NK cells from day 7 onwards compared with the ischemia and MSC-Saline groups (all p<0.05). Repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased splenic NK cells from day 14 onwards compared with the MSC-MSC/once group (all p<0.05) (b). After intramuscular transplantation of hiPSC-MSCs, splenic Tregs were significantly increased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups at day 35 compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased splenic Tregs compared with the ischemia and MSC-Saline groups (all p<0.05). Moreover, repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased splenic Tregs from day 14 onwards compared with the MSC-MSC/once group (all p<0.05) (c).

Splenic Tregs were determined as Foxp3 positive cells in a proportion of pre-gated CD4 positive cells. Our result showed that splenic Tregs reached a peak on day 7 in the MSC-MSC/once group, whereas these immunomodulatory cells continued to increase in the MSC-MSC/week and MSC-MSC/3 days groups. No significant difference was observed between different time points in the ischemia and MSC-Saline groups (Supplementary Fig.4b). Compared with the ischemia group, intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased splenic Tregs on day 35 (Fig.8c, all p<0.05). Intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved splenic Tregs from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.8c, all p<0.05). Repeated systemic intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased splenic Tregs from day 14 onwards compared with the MSC-MSC/once group (Fig.8c, all p<0.05), but there was no significant difference between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.8c, all p>0.05).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs could modulate systemic immune cell activation by decreasing splenic NK cells as well as increasing splenic Tregs. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further decreased splenic NKs and increased splenic Tregs compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

To compare the survival and engraftment of intramuscularly transplanted hiPSC-MSCs with intervenous infusion of hiPSC-MSCs and subcutaneous administration of cyclosporine A, fluorescent imaging of ischemic hind limb was performed immediately and every week in the MSC-Saline-Cyc, MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups (Supplementary Fig.5a). There was no significant difference in cellular engraftment between the MSC-MSC/once and MSC-Saline-Cyc groups through this study (Supplementary Fig.5b, p>0.05). Although repeated intravenous infusion of hiPSC-MSCs without subcutaneous administration of cyclosporine A remarkedly increased cell engraftment in the MSC-MSC/week group relative to the MSC-MSC/once group (Supplementary Fig.5b, p<0.05), no significant difference was observed after subcutaneous administration of cyclosporine A between the MSC-MSC/week-Cyc and MSC-MSC/once-Cyc groups (Supplementary Fig.5b, p>0.05). Nonetheless, subcutaneous administration of cyclosporine A did not improve the cell engraftment in the MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups relative to the MSC-MSC/once and MSC-MSC/week groups respectively (Supplementary Fig.5b, p>0.05).

To compare the therapeutic efficacy of intramuscularly transplanted hiPSC-MSCs with intervenous infusion of hiPSC-MSCs and subcutaneous administration of cyclosporine A, serial laser doppler imaging and analysis was performed to evaluate the blood perfusion and monitor the blood flow recovery in the ischemic hind limb (Supplementary Fig.6a). When comparison between the MSC-MSC/once and MSC-Saline-Cyc groups was performed, intravenous infusion of hiPSC-MSCs significantly improved blood perfusion in the MSC-MSC/once group relative to MSC-Saline-Cyc group during the first 2 weeks (Supplementary Fig.6b, p<0.05). Following intramuscular hiPSC-MSC transplantation at day 7, blood perfusion progressly increased in the MSC-MSC/once and MSC-Saline-Cyc groups. Nevertheless, no significant difference was observed between the MSC-MSC/once and MSC-Saline-Cyc groups from day 21 onwards (Supplementary Fig.6b, p>0.05). Repeated intravenous infusion of hiPSC-MSCs with or without subcutaneous administration of cyclosporine A significantly improved blood perfusion at day 35 in the MSC-MSC/week and MSC-MSC/week-Cyc groups compared with the MSC-MSC/once and MSC-MSC/once-Cyc groups respectively (Supplementary Fig.6b, p<0.05). Nonetheless, subcutaneous administration of cyclosporine A did not improve the blood perfusion in the MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups relative to the MSC-MSC/once and MSC-MSC/week groups respectively (Supplementary Fig.6b, p>0.05).

Cumulatively, our results demonstrated that no significant difference was observed in cell engraftment between a single or repeated intravenous hiPSC-MSC infusion and subcutaneous administration of cyclosporine A. Although there was no significant difference in blood perfusion between the cyclosporine A and single hiPSC-MSC infusion, a significantly improved blood perfusion was observed in the repeated hiPSC-MSC infusion groups relative to the cyclosporine A group. Furthermore, subcutaneous administration of cyclosporine A did not further increased cell engraftment or therapeutic efficacy in either single or repeated hiPSC-MSC infusion groups.

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Repeated intravenous administration of hiPSC-MSCs enhance the efficacy of cell-based therapy in tissue regeneration | Communications Biology -...

SOMERVILLE, Mass.--(BUSINESS WIRE)--Cellarity, a life sciences company founded by Flagship Pioneering to transform the way medicines are created, announced today the release of a unique single-cell dataset to accelerate innovation in mapping multimodal genetic information across cell states and over time. This dataset will be used to power a competition hosted by Open Problems in Single-Cell Analysis.

Cells are among the most complex and dynamic systems and are regulated by the interplay of DNA, RNA, and proteins. Recent technological advances have made it possible to measure these cellular features and such data provide, for the first time, a direct and comprehensive view spanning the layers of gene regulation that drive biological systems and give rise to disease.

Advancements in single-cell technologies now make it possible to decode genetic regulation, and we are excited to generate another first-of-its-kind dataset to support Open Problems in Single Cell Analysis, said Fabrice Chouraqui, PharmD, CEO of Cellarity and a CEO-Partner at Flagship Pioneering. Developing new machine learning algorithms that can predict how a single-cell genome can drive a diversity of cellular states will provide new insights into how cells and tissues move from health to disease and support informed design of new medicines.

To drive innovation for such data, Cellarity generated a time course profiling in vitro differentiation of blood progenitors, a dataset designed in collaboration with scientists at Yale University, Chan Zuckerberg Biohub, and Helmholtz Munich. This time course will be used to power a competition to develop algorithms that learn the underlying relationships between DNA, RNA, and protein modalities across time. Solving this open problem will help elucidate complex regulatory processes that are the foundation for cell differentiation in health and disease.

While multimodal single-cell data is increasingly available, methods to analyze these data are still scarce and often treat cells as static snapshots without modeling the underlying dynamics of cell state, said Daniel Burkhardt, Ph.D., cofounder of Open Problems in Single-Cell Analysis and Machine Learning Scientist at Cellarity. New machine learning algorithms are needed to learn the rules that govern complex cell regulatory processes so we can predict how cell state changes over time. We hope these new algorithms can augment the value of existing or future single-modality datasets, which can be cost effectively generated at higher quality to streamline and accelerate research.

In 2021, Cellarity partnered with Open Problems collaborators to develop the first benchmark competition for multimodal single-cell data integration using a first-of-its-kind multi-omics benchmarking dataset (NeurIPS 2021). This dataset was the largest atlas of the human bone marrow measured across DNA, RNA, and proteins and was used to predict one modality from another and learn representations of multiple modalities measured in the same cells. The 2021 competition saw winning submissions from both computational biologists with deep single-cell expertise and machine learning practitioners for whom this competition marked their first foray into biology. This translation of knowledge across disciplines is expected to drive more powerful algorithms to learn fundamental rules of biology.

For 2022, Cellarity and Open Problems are extending the challenge to drive innovation in modeling temporal single-cell data measured in multiple modalities at multiple time points. For this years competition, Cellarity generated a 300,000-cell time course dataset of CD34+ hematopoietic stem and progenitor cells (HSPC) from four human donors at five time points. HSPCs are stem cells that give rise to all other cells in the blood throughout adult life, and a 10-day time course captures important biology in CD34+ HSPCs. Being able to solve the prediction problems over time is expected to yield new insights into how gene regulation influences differentiation.

Entries to the competition will be accepted until November 15, 2022. For more information, visit the competition page on Kaggle.

About Open Problems in Single Cell Analysis

Open Problems in Single-Cell Analysis was founded in 2020 bringing together academic, non-profit, and for-profit institutions to accelerate innovation in single-cell algorithm development. An explosion in single-cell analysis algorithms has resulted in more than 1,200 methods published in the last five years. However, few standard benchmarks exist for single-cell biology, both making it difficult to identify top performing algorithms and hindering collaboration with the machine learning community to accelerate single-cell science. Open Problems is a first-of-its-kind international consortium developing a centralized, open-source, and continuously updated framework for benchmarking single-cell algorithms to drive innovation and alignment in the field. For more information, visit https://openproblems.bio/.

About Cellarity

Cellaritys mission is to fundamentally transform the way medicines are created. Founded by Flagship Pioneering in 2017, Cellarity has developed unique capabilities combining high-resolution data, single cell technologies, and machine learning to encode biology, predict interventions, and purposefully design breakthrough medicines. By focusing on the cellular changes that underlie disease instead of a single target, Cellaritys approach uncovers new biology and treatments and is applicable to a vast array of disease areas. The company currently has programs underway in metabolic disease, hematology, immuno-oncology, and respiratory disease. For more info, visit http://www.cellarity.com.

About Flagship Pioneering

Flagship Pioneering conceives, creates, resources, and develops first-in-category bioplatform companies to transform human health and sustainability. Since its launch in 2000, the firm has, through its Flagship Labs unit, applied its unique hypothesis-driven innovation process to originate and foster more than 100 scientific ventures, resulting in more than $100 billion in aggregate value. To date, Flagship has deployed over $2.9 billion in capital toward the founding and growth of its pioneering companies alongside more than $19 billion of follow-on investments from other institutions. The current Flagship ecosystem comprises 41 transformative companies, including Denali Therapeutics (NASDAQ: DNLI), Evelo Biosciences (NASDAQ: EVLO), Foghorn Therapeutics (NASDAQ: FHTX), Moderna (NASDAQ: MRNA), Omega Therapeutics (NASDAQ: OMGA), Rubius Therapeutics (NASDAQ: RUBY), Sana Biotechnology (NASDAQ: SANA), and Seres Therapeutics (NASDAQ: MCRB).

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