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A ‘cardiac patch with bioink’ developed to repair heart — ScienceDaily

The heart is the driving force of circulating blood in the body and pumps blood to the entire body by repeating contraction and relaxation of the heart muscles continuously. Human stem cells are used in the clinical therapies of a dead heart, which happens when a blood vessel is clogged or whole or a part of heart muscles is damaged. The clinical use of human bone marrow-derived mesenchymal stem cells (BM-MSCs) have been expanded but failure of the transplanted stem cells in the heart still remains a problem. Recently, an international joint research team of POSTECH, Seoul St. Mary’s Hospital, and City University of Hong Kong developed a ‘cardiac patch with bioink’ that enhanced the functionality of stem cells to regenerate blood vessels, which in turn improved the myocardial infarction affected area.

The joint research team consisted of Prof. Jinah Jang and Dr. Sanskrita Das of POSTECH Creative IT Engineering, Mr. Seungman Jung of POSTECH School of Interdisciplinary Bioscience and Bioengineering, Prof. Hun-Jun Park, Mr. Bong-Woo Park, and Ms. Soo-Hyun Jung of The Catholic University, and Prof. Kiwon Ban and his fellows from City University of Hong Kong. The team mixed genetically engineered stem cells (genetically engineered hepatocyte growth factor-expressing MSCs, HGF-eMSCs) developed by SL Bigen. Co., Ltd to make bioink in the form of a patch and introduced a new therapy by transplanting it to a damaged heart. They called this new strategy as ‘in vivo priming’. The name came from the principle that maximized function of mesenchymal stem cells are maintained in vivo as well as through its exposure to the growth factor secreted by the genetically engineered stem cells.

The joint research team first genetically engineered the existing BM-MSCs to produce hepatocyte growth factor consistently to improve the therapeutic potential of stem cells. The engineered stem cells (HGF-eMSCs) were then mixed with BM-MSCs to make the bioink. They transplanted the cardiac patch with this bioink to the heart muscles affected by myocardial infarction. Considering the limited amount of cells that could be transferred, they used heart-derived extracellular matrix bioink to make a cardiac patch.

Implanted cells in a patch survived longer in vivo and had more myocardiocytes survived than the only BM-MSCs transplanted experimental group. This was because the secretion of cytokine, which helps formation of blood vessels and cell growth was maximized and delivered nutrients fluently that promoted vascular regeneration and enhanced survival of the myocardiocytes.

The research team anticipated that this new method could be a breakthrough treatment of myocardial infarction as the implanted stem cells through HGF-eMSCs ultimately enhanced vascular regeneration and improved the myocardial infarction affected area.

“We can augment the function of adult stem cells approved by Ministry of Food and Drug Safety and FDA using this newly developed and promising 3D bioprinting technology with the engineered stem cells. It is our goal to develop a new concept of medicine for myocardial infarction in the near future,” said Prof. Jinah Jang who led the research.

POSTECH began to develop medicine for cardiovascular diseases based on this newly developed bioprinting method with the research team from The Catholic University in 2017. Now, it is being tested in animals for efficacy evaluation with Chonnam National University. Also, the technology is already transferred to T&R Biofab, which is a company developing 3D printers, software, and bioinks to print cells.

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Advances in production of retinal cells for treating blindness — ScienceDaily

Researchers at Karolinska Institutet and St Erik Eye Hospital in Sweden have discovered a way to refine the production of retinal cells from embryonic stem cells for treating blindness in the elderly. Using the CRISPR/Cas9 gene editing, they have also managed to modify the cells so that they can hide from the immune system to prevent rejection. The studies are published in the scientific journals Nature Communications and Stem Cell Reports.

Age-related macular degeneration of the eye is the most common cause of blindness in the elderly. This loss of vision is caused by the death of the photoreceptors (the rods and cones) resulting from the degeneration and death of the underlying retinal pigment epithelial (RPE cells), which provide the rods and cones vital nourishment. A possible future treatment could be to transplant fresh RPE cells formed from embryonic stem cells.

Working with colleagues at St Erik Eye Hospital, researchers at Karolinska Institutet have now found specific markers on the surface of the RPE cells that can be used to isolate and purify these retinal cells. The results are published in Nature Communications.

“The finding has enabled us to develop a robust protocol that ensures that the differentiation of embryonic stem cells into RPE cells is effective and that there is no contamination of other cell types,” says principal investigator Fredrik Lanner, researcher at the Department of Clinical Science, Intervention and Technology and the Ming Wai Lau Center for Reparative Medicine at Karolinska Institutet. “We’ve now begun the production of RPE cells in accordance with our new protocol for the first clinical study, which is planned for the coming years.”

One obstacle when transplanting tissue generated from stem cells is the risk of rejection, which occurs if transplantation antigens of the donor and patient tissue differ. Research groups around the world are therefore working on creating what are known as universal cells, which ideally will not trigger an immune response.

In a study published in Stem Cell Reports the same group at Karolinska Institutet created embryonic stem cells able to hide from the immune system. Using CRISPR/Cas9 gene editing, they removed certain molecules, HLA class I and class II, which sit on the surface of the stem cells as a means by which the immune system can identify them as endogenous or not. The stem cells lacking these molecules were then differentiated into RPE cells.

The researchers have been able to show that the modified RPE cells retain their character, that no harmful mutations appear in the process and that the cells can avoid the immune system’s T cells without activating other immune cells. The rejection response was also significantly less and more delayed than after the transplantation of regular RPE cells, the surfaces of which still possess HLA molecules.

“The research is still in an early stage, but this can be an important initial step towards creating universal RPE cells for the future treatment of age-related macular degeneration,” says joint last author Anders Kvanta, adjunct professor at the Department of Clinical Neuroscience and consultant at St Erik Eye Hospital.

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Scientists explore newborn, regenerated neurons — ScienceDaily

The zebrafish is a master of regeneration: If brain cells are lost due to injury or disease, it can simply reproduce them — contrary to humans where this only happens in the fetal stage. However, the zebrafish is evolutionarily related to humans and, thus, possesses the same brain cell types as humans. Can a hidden regeneration potential also be activated in humans? Are therapies for stroke, craniocerebral trauma and presently incurable diseases such as Alzheimer’s and Parkinson’s possible?

Dresden scientists have succeeded in determining the number and type of newly formed neurons in zebrafish; practically conducting a “census” in their brains. Following an injury, zebrafish form new neurons in high numbers and integrate them into the nervous system, which is the reason for their amazing brain regeneration ability. The study was conducted as a collaboration project “made in Dresden”: Scientists from the Center for Regenerative Therapies TU Dresden (CRTD) combined their expertise in stem cell biology with the latest methods from the DRESDEN-concept Genome Center and complex bio-informatic analyses from the Max Planck Institute for the Physics of Complex Systems and the Center for Systems Biology Dresden. They have now published their results in the scientific journal DEVELOPMENT, which reports on topics of developmental, stem cell and regenerative biology.

For their study, the team led by Dr. Christian Lange and Prof. Dr. Michael Brand from the CRTD used adult transgenic zebrafish in whose forebrain they were able to identify the newborn neurons. The forebrain of the zebrafish is the equivalent to the human cerebral cortex, the largest and functionally most important part of the brain. The Dresden research team investigated the newborn and mature neurons as well as brain stem cells using single cell sequencing. Thus, they discovered specific markers for newborn neurons and were able to comprehensively analyse which types of neurons are newly formed in the adult brain of the zebrafish.

The scientists discovered two types of neurons that can be newly formed: Projection neurons, which create connections between brain areas, and internal neurons, which serve to fine-tune the activity of the projection neurons. The researchers also investigated the data obtained from brain cell sequencing of mice and found that zebrafish and mice have the same cell types. This also makes these results highly relevant for humans.

“On the basis of this study, we will further investigate the regeneration processes that take place in zebrafish. In particular, we will study the formation of new neurons after traumatic brain damage and their integration,” explains Prof. Dr. Michael Brand, CRTD Director and senior author of the study. “We hope to gain insights that are relevant for possible therapies helping people after injuries and strokes or suffering from neurodegenerative diseases. We already know that a certain regenerative ability is also present in humans and we are working on awakening this potential. The results of our study are also important for understanding the conditions under which transplanted neurons can network with the existing ones and thus could let humans re-gain their former mental performance.”

The CRTD at TU Dresden is the academic home for scientists from more than 30 nations. Their mission is to discover the principles of cell and tissue regeneration and leveraging this for recognition, treatment and reversal of diseases. The CRTD links the bench to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene-editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, haematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases. The group of Prof. Dr. Michael Brand investigates the patterning and regeneration of the vertebrate brain and eye.

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New mechanism for regulating the activity of stem cells discovered — ScienceDaily

Scientists from the German Cancer Research Center (DKFZ) and the Heidelberg Institute of Stem Cell Technology and Experimental Medicine (HI-STEM) and the Max Planck Institute in Freiburg have identified a new control mechanism that enables stem cells to adapt their activity in emergency situations. For this purpose, the stem cells simultaneously modify the blueprints for hundreds of proteins encoded in the gene transcripts. In this way, they control the amount of protein produced and can also control the formation of certain proteinisoforms. If this mechanism is inactivated, stem cells lose their self-renewal potential and can no longer react adequately to danger signals or inflammation.

Messenger RNA molecules (mRNAs), the transcripts of genes, serve as the blueprint for the construction of proteins. In all higher organisms, the cell attaches a long chain of adenine nucleotides, the so-called poly(A) tail, to the rear end of the transcripts in a process known as polyadenylation. The length and position of the chain varies from organism to organism and serves to stabilize the RNA molecule.

Different signaling motifs show the participating enzymes the site where the poly(A) chain is to be attached to the transcript. This does not always happen at the same site of the mRNA. The differential use of these sites is known as “alternative polyadenylation.” This mechanism affects the length of the so-called 3′-untranslated end of the mRNA, a region that contains information beyond the protein sequence. This 3′-untranslated region is particularly important for stability, localisation and the efficiency with which the transcripts are translated into proteins. “Only recently it has been known that some cell types use this mechanism to control how much protein is produced per transcript and which isoform is to be expressed,” says Pia Sommerkamp, the lead author of the study conducted by DKFZ and HI-STEM.

By applying a novel sequencing method, the scientists were able to identify numerous genes that are essential for stem cell development and are regulated via alternative polyadenylation during differentiation or in response to inflammation. These include the central metabolic enzyme glutaminase, which can be produced in two differently active isoforms. As the researchers found out, the activation of blood stem cells leads to a change from the less active to the highly active glutaminase isoform. This switch is coordinated by alternative polyadenylation.

“Only this isoform switch enables the stem cells to adapt all the necessary metabolic pathways according to their needs. This includes rapid increases in activity that are necessary in the case of infections or inflammations,” explains Nina Cabezas-Wallscheid, who was co-supervisor of the study at the MPI in Freiburg. “With alternative polyadenylation, we have now discovered another control level with which stem cells regulate vital processes. We now want to investigate in more detail whether cancer stem cells also use this mechanism for their own purposes in leukemias. We hope that this will provide us with new approaches for fighting the disease,” explains Andreas Trumpp, Director of HI-STEM gGmbH at DKFZ and senior author of the study.

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Human immune cells produced in a dish in world first — ScienceDaily

One day the advance could lead to a patient’s own skin cells being used to produce new cells for cancer immunotherapy or to test autoimmune disease interventions.

The group, led by Professors Ed Stanley and Andrew Elefanty, from the Murdoch Children’s Research Institute in Melbourne, Australia, said the work has added definitive evidence about how the body’s earliest immune cells are formed.

These lymphocytes are produced by cells which form the embryo’s first organs rather than the blood-producing stem cells that sit inside the body’s bone marrow.

The research combined two powerful laboratory techniques, genetic engineering and a novel way of growing stem cells, to make the breakthrough, which has been published in the  journal Nature Cell Biology.

First, the team engineered pluripotent stem cells to glow green when a specific protein marker of early immune cells, RAG1, was switched on. RAG1 is responsible for creating the immune response to infections and vaccines.

Next, the team isolated the glowing green RAG1-positive cells and showed that they could also form multiple immune cell types, including cells required for shaping the development of the whole immune system.

“We think these early cells might be important for the correct maturation of the thymus, the organ that acts as a nursery for T-cells” said Professor Stanley.

“These RAG1 cells are like the painters and decorators who set up that nursery, making it a safe and cozy environment for later-born immune cells,” he said.

Professor Elefanty said, “Although a clinical application is likely still years away, we can use this new knowledge to test ideas about how diseases like childhood leukemia and type 1 diabetes develop. Understanding more about the steps these cells go through, and how we can more efficiently nudge them down a desired pathway, is going to be crucial to that process.”

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In a first, researchers unveil stem cell models of human spine development — ScienceDaily

More than 20 years ago, the lab of developmental biologist Olivier Pourquié discovered a sort of cellular clock in chicken embryos where each “tick” stimulates the formation of a structure called a somite that ultimately becomes a vertebra.

In the ensuing years, Pourquié and others further illuminated the mechanics of this so-called segmentation clock across many organisms, including creation of the first models of the clock in a lab dish using mouse cells.

While the work has improved knowledge of normal and abnormal spine development, no one has been able to confirm whether the clock exists in humans — until now.

Pourquié led one of two separate teams reporting Jan. 8 in Nature that after decades of effort, they have created the first lab-dish models of the segmentation clock that use stem cells derived from adult human tissue.

The achievements not only provide the first evidence that the segmentation clock ticks in humans but also give the scientific community the first in vitro systems enabling the study of very early spine development in humans.

“We know virtually nothing about human development of somites, which form between the third and fourth week after fertilization, before most people know they’re pregnant,” said Pourquié, professor of genetics in the Blavatnik Institute at Harvard Medical School and a principal faculty member of the Harvard Stem Cell Institute. “Our system should be a powerful one to study the underlying regulation of the segmentation clock.”

“Our innovative experimental system now allows us to compare mouse and human development side by side,” said Margarete Diaz-Cuadros, a graduate student in the Pourquié lab and co-first author of the Harvard Medical School-led study. “I am excited to unravel what makes human development unique.”

Both models open new doors for understanding developmental conditions of the spine, such as congenital scoliosis, as well as diseases involving tissues that arise from the same region of the embryo, known as the paraxial mesoderm. These include skeletal muscle and brown fat in the entire body, as well as bones, skin and lining of blood vessels in the trunk and back.

Pourquié hopes that researchers will be able to use the new stem cell models to generate differentiated tissue for research and clinical applications, such as skeletal muscle cells to study muscular dystrophy and brown fat cells to study type 2 diabetes. Such work would provide a foundation for devising new treatments.

“If you want to generate systems that are useful for clinical applications, you need to understand the biology first,” said Pourquié, who is also the Harvard Medical School Frank Burr Mallory Professor of Pathology at Brigham and Women’s Hospital. “Then you can make muscle tissue and it will work.”

Although scientists have derived many kinds of tissue by reprogramming adult cells into pluripotent stem cells and then coaxing them along specific developmental paths, musculoskeletal tissue proved stubborn. In the end, however, Pourquié and colleagues discovered that they could facilitate the transformation by adding just two chemical compounds to the stem cells while they were bathed in a standard growth culture medium.

“We can produce paraxial mesoderm tissue with about 90 percent efficiency,” said Pourquié. “It’s a remarkably good start.”

His team created a similar model derived from embryonic mouse cells.

The HMS researchers were surprised to find that the segmentation clock began ticking in both the mouse and human cell dishes and that the cells didn’t first need to be arranged on a 3D scaffold more closely resembling the body.

“It’s pretty spectacular that it worked in a two-dimensional model,” said Pourquié. “It’s a dream system.”

The team found that the segmentation clock ticks every 5 hours in the human cells and every 2.5 hours in the mouse cells. The difference in frequency parallels the difference in gestation time between mice and humans, the authors said.

Among the next projects for Pourquié’s lab are investigating what controls the clock’s variable speed and, more ambitiously, what regulates the length of embryonic development in different species.

“There are many very interesting problems to pursue,” he said.

A third group publishing in the same issue of Nature uncovered new insights into how cells synchronize in the segmentation clock using mouse embryos engineered to incorporate fluorescent proteins.

Pourquié is senior author of the HMS-led paper. Postdoctoral researcher Daniel Wagner of HMS is co-first author. Additional authors are affiliated with Kyoto University, RIKEN Center for Brain Science and Brandeis University.

Pourquié has started a company called Anagenesis Biotechnologies based on protocols developed for this study. It uses high-throughput screening to search for cell therapies for musculoskeletal diseases and injuries.

This work was funded by National Institutes of Health grant 5R01HD085121.

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Plant-derived SVC112 hits cancer stem cells, leaves healthy cells alone — ScienceDaily

The red, tube-shaped flowers of the firecracker bush (Bouvardia ternifolia), native to Mexico and the American Southwest, attract hummingbirds. The bush also provides the chemical bouvardin, which the lab of University of Colorado Cancer Center and CU Boulder researcher, Tin Tin Su, PhD, and others have shown to slow a cancer’s ability to make proteins that tell cancer cells to grow and spread. Now a paper based on nearly half a decade of work, published in the journal Cancer Research, shows that the molecule SVC112, based on bouvardin and synthesized by Su’s Colorado-based pharmaceutical startup, SuviCa, Inc. acts specifically against head and neck cancer stem cells (CSCs), resulting in better tumor control with less toxicity to healthy cells than existing, FDA-approved protein synthesis inhibitors. The group hopes these promising preclinical results will lay the groundwork for human clinical trials of SVC112 in head and neck cancer patients.

“Proteins are the keys to initiating genetic programs in the cells to tell them Now you grow, now you stay put, now you metastasize. And those proteins are called transcription factors,” says paper co-senior author, Antonio Jimeno, MD, PhD, director of the Head and Neck Cancer Clinical Research Program and co-leader of the Developmental Therapeutics Program at CU Cancer Center, member of the Gates Center for Regenerative Medicine, and the Daniel and Janet Mordecai Endowed Chair for Cancer Stem Cell Research at the CU School of Medicine.

Cancer stem cells (CSCs) are a subpopulation of cancer cells that, like healthy stem cells, act as factories, manufacturing cells that make up the bulk of a cancer’s tissue. Unfortunately, CSCs often resist treatments like radiation and chemotherapy, and can survive to restart tumor growth once treatment ends.

“Many groups have linked the production of transcription factors to the survival and growth of cancer stem cells, but inhibitors have just been too toxic — they come with too many side effects. Definitely our studies suggest that this drug could be an advantage over existing drugs. It inhibits protein synthesis in a way that no other drug does and that’s why we’re excited,” says Su, who is also co-leader of the CU Cancer Center Molecular and Cellular Oncology Program.

Importantly, the group’s work showed that SVC112 acts specifically against proteins like Myc and Sox2 needed by cancer stem cells, while leaving healthy cells relatively unharmed. They did this by comparing the effects of the drug in “matched pairs” of cancer cells and healthy cells grown from samples graciously donated by five head and neck cancer patients in Colorado. For further comparison, the group did the same experiments with the FDA-approved protein synthesis inhibitor known as omacetaxine mepesuccinate (also called homoharringtonin, or HHT).

“Having cancer cells along with matched non-cancer cells from the same patient is pretty unique. When we tested these matched pairs with SVC112 and with HHT, what we saw is the approved drug eliminated both cancer and normal cells, whereas SVC112 had selectivity — it affected cancer cells but not healthy cells — so theoretically the effects on the normal tissue will be less,” Su says. In fact, healthy cells were between 3.8 and 5.6 times less sensitive to SVC112 than were cancer cells (healthy cells and cancer cells were equally sensitive to the FDA-approved drug HHT).

The next step was using SVC112 to treat head and neck tumors grown in mouse models from samples of human tumors. Earlier work had shown that SVC112 sensitized previously radiation-resistant CSCs to radiation treatment, and so the group tested SVC112 and radiation alone and in combination.

“What we saw is that only when you decrease the population of cancer stem cells to under 1 percent of the total makeup of a tumor did the tumor shrink,” Jimeno says. “It’s like cancer stem cells are in the control tower, directing the growth of the tumor. If you impair enough of these directors, other cancer cells don’t know what to do and cancer growth slows down or stops.”

Ongoing work continues in two major directions, with Su’s team continuing to propel the drug toward the clinic and Jimeno’s team working to understand of the basic biology driving the drug’s action, how to best combine it with other treatments such as radiation or immunotherapy, and its potential uses in other cancer types.

“This is the first report of the drug, from the drug’s chemical structure, its basic effects on commercial cell lines, to its mechanism of action with patient-derived cell lines and more complex action on CSCs, all the way to animal models from patient samples,” Jimeno says.

Early drug development undertaken outside the funding structure of established pharmaceutical sponsors often requires contributions from many sources, and the current project is no exception, receiving support from subcontracts to SuviCa’s Small Business Innovation Research (SBIR) award, a National Institutes of Health grant to the Su lab, pilot funding from the CU Cancer Center, and philanthropy support from the Gates Center and the CU School of Medicine.

“We are so grateful for the belief from all these organizations and individuals, and especially to our patients, whose courage has been essential in making the models we need to test this new drug,” says Jimeno.

Proposals are already underway to take the next important step: Testing SVC112 in an early human clinical trial.

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Diabetes drug could lead to new treatment — ScienceDaily

A drug designed to tackle diabetes could also be repurposed as the first treatment to prevent miscarriage by targeting the lining of the womb itself, according to a clinical trial led by the University of Warwick.

The treatment works by increasing the amount of stem cells in the lining of the womb, improving conditions in the womb to support pregnancy.

The research by Warwick Medical School is reported today (9 January) in the journal EBioMedicine from research conducted with University Hospitals Coventry and Warwickshire and supported by the NIHR Coventry and Warwickshire Clinical Research Facility. The research was funded by and took place at Tommy’s National Miscarriage Research Centre.

Recurrent miscarriage is defined as the loss of two or more consecutive pregnancies, with additional miscarriages decreasing the likelihood of a successful pregnancy. Previous research by the Warwick team revealed that a lack of stem cells in the womb lining is causing thousands of women to suffer from recurrent miscarriages. The team also demonstrated that stem cells protect specialised cells, called decidual cells, from excessive stress and inflammation. Decidual cells surround the implanting embryo and excessive stress can cause breakdown of the womb lining in pregnancy.

A new class of diabetes drugs called gliptins targets an enzyme involved in the recruitment of circulating stem cells to the womb. The researchers investigated whether inhibiting this enzyme, called DPP4, using a particular drug, sitagliptin, would improve conditions in the womb for pregnancy.

In a pilot clinical trial, thirty-eight women aged 18 to 42 who had experienced a large number of recurrent miscarriages (average five) were given either an oral course of sitagliptin or a placebo for three menstrual cycles. Biopsies of the womb were taken at the start of the course of treatment and afterwards to determine the number of stem cells present before and after the course.

They found an average increase in stem cell count of 68% in those women who took the full course of sitagliptin. This compares to no significant increase in those in the control group receiving an identical placebo pill. They also saw a 50% decrease in the number of ‘stressed’ cells present in the lining of the womb. There were minimal side effects for the participants.

The researchers now hope to take the treatment to clinical trial and, if successful, it would be the first targeted specifically at the lining of the womb to prevent miscarriage.

Professor Jan Brosens, of Warwick Medical School and Consultant in Reproductive Health at University Hospitals Coventry and Warwickshire NHS Trust, said: “There are currently very few effective treatments for miscarriage and this is the first that aims at normalising the womb before pregnancy. Although miscarriages can be caused by genetic errors in the embryo, an abnormal womb lining causes the loss of chromosomal normal pregnancies. We hope that this new treatment will prevent such losses and reduce both the physical and psychological burden of recurrent miscarriage.”

Professor Siobhan Quenby from Warwick Clinical Trials Unit and an Honorary Consultant at University Hospital Coventry and Warwickshire NHS Trust, said: “We have improved the environment that an embryo develops in and in doing so we hope to improve the chances of a successful pregnancy. Although this research was specifically designed to test whether we could increase the presence of stem cells in the womb, follow-up of participants found that there were no further losses of normal pregnancies in those who took sitagliptin. These are very early results and the treatment now needs to be further tested in a large-scale clinical trial.”

Jane Brewin, Chief Executive at Tommy’s said: “For far too long it has often been said by many health professionals that miscarriage is not preventable, and parents have been left with little hope given the paucity of treatment options available. This situation prompted Tommy’s to invest in the Tommy’s National Centre for Miscarriage Research and this breakthrough research by the world leading team at Warwick shows great promise for an effective treatment which will reduce miscarriage and possibly later pregnancy loss too. A large-scale trial is needed to verify the findings and we hope that this will get underway quickly.”

Stem cells play a key role in creating the decidual cells in the womb lining which support the placenta throughout pregnancy. Insufficient stem cells in the womb lining leads to an excess of stressed and inflammatory decidual cells, which in turn may cause placental bleeding and miscarriage. Sitagliptin was effective not only in increasing stem cells in the womb lining but also decreasing the abundance of stressed decidual cells.

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Discovery could lead to better understanding of poor wound healing in diabetic patients — ScienceDaily

A team of University of California, Irvine researchers have published the first comprehensive overview of the major changes that occur in mammalian skin cells as they prepare to heal wounds. Results from the study provide a blueprint for future investigation into pathological conditions associated with poor wound healing, such as in diabetic patients.

“This study is the first comprehensive dissection of the major changes in cellular heterogeneity from a normal state to wound healing in skin,” said Xing Dai, PhD, a professor of biological chemistry and dermatology in the UCI School of Medicine, and senior author. “This work also showcases the collaborative efforts between biologists, mathematician and physicists at UCI, with support from the National Institute of Arthritis & Musculoskeletal & Skin Diseases-funded UCI Skin Biology Resource-based Center and the NSF-Simons Center for Multiscale Cell Fate Research.

The study, titled, “Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics,” was published this week in Cell Reports.

“Our research uncovered at least four distinct transcriptional states in the epidermal basal layer as part of a ‘hierarchical-lineage’ model of the epidermal homeostasis, or stable state of the skin, clarifying a long-term debate in the skin stem cell field,” said Dai.

Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, the team identified three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization, which is the process by which the skin and mucous membranes replace superficial epithelial cells damaged or lost in a wound.

Epithelial tissue maintenance is driven by resident stem cells, the proliferation and differentiation dynamics of which need to be tailored to the tissue’s homeostatic and regenerative needs. However, our understanding of tissue-specific cellular dynamics in vivo at single-cell and tissue scales is often very limited.

“Our study lays a foundation for future investigation into the adult epidermis, specifically how the skin is maintained and how it can robustly regenerate itself upon injury,” said Dai.

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Study in mouse, human cells suggests unique anti-cancer properties of such a therapy — ScienceDaily

Immunotherapy that involves treating cancer with the body’s own immune cells, or those of a matched donor, shows promise in clinical trials for some patients, but not all.

A new study from Washington University School of Medicine in St. Louis suggests that the age of certain immune cells used in such therapy plays a role in how effective the immunotherapy is. These cells — natural killer (NK) cells — appear to be more effective the earlier they are in development, opening the door to the possibility of an immunotherapy that would not utilize cells from the patient or a matched donor. Instead, they could be developed from existing supplies of what are called human pluripotent stem cells.

“We are trying to improve the effectiveness of immunotherapy for more patients,” said senior author Christopher M. Sturgeon, PhD, an assistant professor of medicine. “This special source of natural killer cells has the potential to fill some of the gaps remaining with adult NK cell therapy. There is early evidence that they are more consistent in their effectiveness, and we would not need to process cells from a donor or the patient. They could be manufactured from existing cell supplies following the strict federal guidelines for good manufacturing practices. The characteristics of these cells let us envision a supply of them ready to pull off the shelf whenever a patient needs them.”

Unlike the adult versions of NK cells used in most investigational therapies, earlier versions of such cells do not originate from bone marrow. Rather, these NK cells are a special type of short-lived immune cell that forms in the yolk sac of the early mammalian embryo. But for therapeutic purposes, such cells do not need to originate from embryos — they can be developed from human pluripotent stem cells, which have the ability to give rise to many different cell types, including these specialized natural killer cells. Manufacturing such cells — which many academic medical centers already have the ability to do — would make them available quickly, eliminating the time needed to process the patient’s or donor’s cells, which can take weeks.

The study appears March 19 in the journal Developmental Cell.

“Before a certain time point in early development, there is no such thing as bone marrow, but there is still blood being made in the embryo,” Sturgeon said. “It’s a transient wave of blood that the yolk sac makes to keep the embryo going until bone marrow starts to form. And that’s the blood cell generation that’s making these unique natural killer cells. This early blood appears to be capable of things that adult blood simply can’t do.”

Studying mouse and human induced pluripotent stem cells that have been coaxed into forming these unique NK cells, the researchers showed that the NK cells are better at releasing specific anti-tumor chemicals — a process called degranulation — than their adult counterparts. Even NK cells derived from umbilical cord blood do not respond as robustly. NK cells of adult origin also release different chemicals that trigger harmful inflammation, but this response is not necessarily effective against cancer.

Past work by other groups suggested NK cells from earlier development might be more effective, but how and why this was the case remained unknown. The specific origin of these cells was also a mystery.

“Now we know where these special natural killer cells come from and that we can never get them from an adult donor, only a pluripotent stem cell,” Sturgeon said. “Based on their unique behavior alone, there is one small clinical trial of these cells that is ongoing. Now that we know how to manufacture them and how they work, it opens the door for more trials and for improving upon their function.”

According to Sturgeon, such cells could be produced from existing lines of pluripotent stem cells that would not need to come from a matched donor because, in general, NK cells do not heavily attack the body’s healthy tissues, as many T cell therapies can. T cells are another type of immune cell often used to treat blood cancer as part of a stem cell transplant, commonly called a bone marrow transplant. Even when NK cells do cause harm, they do not stay in the body for long periods of time.

From a basic science standpoint, Sturgeon also is interested in understanding why these cells are present in the early embryo in the first place and where they go in later development and after birth.

“We can only speculate at this point, but it’s possible that during early embryonic development, when there is so much rapid cell division, these cells are there as a surveillance mechanism to protect against pediatric cancers or infection,” he said.

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Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.

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