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complete muscle replacement and movement achieved in mouse models — ScienceDaily

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When we tear a muscle ” stem cells within it repair the problem. We can see this occurring not only in severe muscle wasting diseases such as muscular dystrophy and in war veterans who survive catastrophic limb injuries, but also in our day to day lives when we pull a muscle.

Also when we age and become frail we lose much of our muscle and our stem cells don’t seem to be able to work as well as we age.

These muscle stem cells are invisible engines that drive the tissue’s growth and repair after such injuries. But growing these cells in the lab and then using them to therapeutically replace damaged muscle has been frustratingly difficult.

Researchers at the Australian Regenerative Medicine Institute at Monash University in Melbourne, Australia have discovered a factor that triggers these muscle stem cells to proliferate and heal. In a mouse model of severe muscle damage, injections of this naturally occurring protein led to the complete regeneration of muscle and the return of normal movement after severe muscle trauma.

The research led by Professor Peter Currie, Director of Monash University’s Australian Regenerative Medicine Institute, is published today in Nature.

The scientists studied the regeneration of skeletal muscle in zebrafish, fast becoming the go-to animal model for the study of stem cell regeneration because but fish are quick to reproduce, easier to experimentally manipulate, and share at least 70 percent of its genes with humans. It is also transparent which allows the scientists to witness the actual regeneration in living muscle.

By studying the cells that migrated to a muscle injury in these fish the scientists identified a group of immune cells, called macrophages, which appeared to have a role in triggering the muscle stem cells to regenerate. “What we saw were macrophages literally cuddling the muscle stem cells, which then started to divide and proliferate. Once they started this process, the macrophage would move on and cuddle then next muscle stem cell, and pretty soon the wound would heal,”? Professor Currie said

Macrophages are the cells that flock to any injury or infection site in the body, removing debris and promoting healing. “They are the clean up crew of the immune system,” Professor Currie said.

It has long been thought that two types of macrophages exist in the body: those that move to the injury rapidly and remove debris, and those that come in slower and stick around doing the longer term clean-up.

The research team, however, found that there were in fact eight genetically different types of macrophages in the injury site, and that one type, in particular, was the “cuddler.” Further investigation revealed that this affectionate macrophage released a substance called NAMPT.

By removing these macrophages from the zebrafish and adding the NAMPT to the aquarium water the scientists found they could stimulate the muscle stem cells to grow and heal ” effectively replacing the need for the macrophages.”

Importantly recent experiments placing a hydrogel patch containing NAPMT into a mouse model of severe muscle wasting led to what Professor Currie called significant replacement of the damaged muscle. The researchers are now in discussions with a number of biotech companies about taking NAMPT to clinical trials for the use of this compound in the treatment of muscle disease and injury.

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Hot nano-chisel used to create artificial bones in a Petri dish — ScienceDaily

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A holy grail for orthopedic research is a method for not only creating artificial bone tissue that precisely matches the real thing, but does so in such microscopic detail that it includes tiny structures potentially important for stem cell differentiation, which is key to bone regeneration.

Researchers at the NYU Tandon School of Engineering and New York Stem Cell Foundation Research Institute (NYSF) have taken a major step by creating the exact replica of a bone using a system that pairs biothermal imaging with a heated “nano-chisel.” In a study, “Cost and Time Effective Lithography of Reusable Millimeter Size Bone Tissue Replicas with Sub-15 nm Feature Size on a Biocompatible Polymer,” which appears in the journal Advanced Functional Materials, the investigators detail a system allowing them to sculpt, in a biocompatible material, the exact structure of the bone tissue, with features smaller than the size of a single protein — a billion times smaller than a meter. This platform, called, bio-thermal scanning probe lithography (bio-tSPL), takes a “photograph” of the bone tissue, and then uses the photograph to produce a bona-fide replica of it.

The team, led by Elisa Riedo, professor of chemical and biomolecular engineering at NYU Tandon, and Giuseppe Maria de Peppo, a Ralph Lauren Senior Principal Investigator at the NYSF, demonstrated that it is possible to scale up bio-tSPL to produce bone replicas on a size meaningful for biomedical studies and applications, at an affordable cost. These bone replicas support the growth of bone cells derived from a patient’s own stem cells, creating the possibility of pioneering new stem cell applications with broad research and therapeutic potential. This technology could revolutionize drug discovery and result in the development of better orthopedic implants and devices.

The research, “Cost and time effective lithography of reusable millimeter size bone tissue replicas with sub-15 nm feature size on a biocompatible polymer,” appears in Advanced Functional Materials.

In the human body, cells live in specific environments that control their behavior and support tissue regeneration via provision of morphological and chemical signals at the molecular scale. In particular, bone stem cells are embedded in a matrix of fibers — aggregates of collagen molecules, bone proteins, and minerals. The bone hierarchical structure consists of an assembly of micro- and nano- structures, whose complexity has hindered their replication by standard fabrication methods so far.

“tSPL is a powerful nanofabrication method that my lab pioneered a few years ago, and it is at present implemented by using a commercially available instrument, the NanoFrazor,” said Riedo. “However, until today, limitations in terms of throughput and biocompatibility of the materials have prevented its use in biological research. We are very excited to have broken these barriers and to have led tSPL into the realm of biomedical applications.”

Its time- and cost-effectiveness, as well as the cell compatibility and reusability of the bone replicas, make bio-tSPL an affordable platform for the production of surfaces that perfectly reproduce any biological tissue with unprecedented precision.

“I am excited about the precision achieved using bio-tSPL. Bone-mimetic surfaces, such as the one reproduced in this study, create unique possibilities for understanding cell biology and modeling bone diseases, and for developing more advanced drug screening platforms,” said de Peppo. “As a tissue engineer, I am especially excited that this new platform could also help us create more effective orthopedic implants to treat skeletal and maxillofacial defects resulting from injury or disease.”

The research was supported by the US Army Research Office, the National Science Foundation (CMMI and CBET programs), the Office of Basic Energy Sciences of the US Department of Energy, the New York Stem Cell Foundation, and the Ralph and Ricky Lauren Family Foundation. The NanoFrazor was acquired through an NSF CMMI MRI grant.

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Identification of three genes that determine the stemness of gastric tissue stem cells — ScienceDaily

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The human body consists of about 60 trillion cells that are renewed day by day to maintain homeostasis of body tissues. In particular, cells of the digestive tract are renewed completely within several weeks thanks to vigorous proliferation where tissue stem cells of every tissue play critical roles in supplying those cells. Tissue stem cells play essential roles in various phenomena such as histogenesis and recovery from damage by producing differentiated cells while dividing. They do this by producing identical cells (self-renewal) or by differentiating into other types of cells. The research team led by Profs. Murakami and Barker of the Cancer Research Institute, Kanazawa University revealed the presence of gastric tissue stem cells expressing the Lgr5 gene*1), a tissue stem cell marker at the gastric gland base in the gastric tissue, the stemness*2) of which could be suppressed by Wnt signaling*3) (Leushacke M. et al., Nat. Cell Biol., 2017). However, due to the technical difficulty of further detailed in vivo verification, most of the molecular mechanisms related to tissue stem cells regulated by Wnt signaling remained a mystery.

The research team investigated the intracellular molecular mechanisms for Wnt signaling-dependent regulation of proliferation and self-renewal of gastric tissue stem cells by using organoids*4) established from mice. These enabled visualization of Lgr5+ gastric tissue stem cells. Further, screening using Genome-Scale CRISPR Knock-Out (GeCKO)*5), which can arbitrarily produce loss-of-function of various genes, allowed the elucidation of molecular mechanisms regulating the Wnt signaling-dependence of gastric tissue stem cells. The team revealed that loss-of-function of Alk, Bclaf3 and Prkra genes induced Wnt signaling-independent proliferation of the organoids. Because these genes are expressed in differentiated cells of mouse gastric tissues but not in stem cells, the team postulated that these genes might negatively regulate the stemness of tissue cells. Further analyses have revealed that Alk suppresses Wnt signaling by phosphorylating Gsk3β, one of the regulatory factors of Wnt signaling. Further, Bclaf3 and Prkra regulate the expression of Reg family genes, which are essential for proliferation of gastric tissue stem cells, by inhibiting expression of epithelial interleukins 11 and 23*6). From these results, Alk, Bclaf3 and Prkra have been identified as the genes that determine the stemness of gastric tissue stem cells.

The present study has elucidated previously unknown molecular mechanisms regulating the self-renewal and differentiation of tissue stem cells, which play roles in tissue homeostasis and recovery from damage. Similar molecular mechanisms may exist and function in other tissue stem cells, since Wnt signaling is widely activated in various stem cells regardless of their developmental stages. It is expected that treatments for tissue damage, not only of the digestive tract but also in liver, kidney and pancreas, should become possible if regulation of the self-renewal and differentiation of stem cells via the regulatory mechanisms described above could be verified in other tissues. The results of the present study provide new insights and technical approaches in stem cell research and are expected to stimulate innovation in the field of regenerative medicine and cancer treatment in the future.

Glossary

*1) Lgr5 gene The gene coding leucine-rich orphan G-protein-coupled receptor5. It is one of the target genes of Wnt signaling that regulates the determination of cell fate and is a marker gene of epithelial stem cells that are necessary for the homeostasis of digestive tract tissues and for the recovery from damage. In recent years, expression of this gene is known in a wide range of epithelial tissues of kidney, lung, liver, uterus, etc. It is also reported as a stem cell marker of colorectal cancers in addition to normal epithelial stem cells.

*2) Stemness Stemness refers to the property of being able to proliferate by cell division while, at the same time, maintaining the ability to differentiate into a variety of cells that form tissues.

*3) Wnt signaling The signaling pathway activated by Wnt protein. Wnt signaling plays important roles in a wide variety of cell processes of ontogeny such as cell fate, proliferation and migration. Mutations of genes associated with Wnt signaling pathway are involved in various hereditary and spontaneously-emerging cancers.

*4) Organoid Organoid refers to an ex vivo three-dimensional cell culture body that possesses structure and functions mimicking those of real tissues and organs. Since an organoid mimicking in vivo properties of a tissue or an organ can be maintained and observed, it is expected that organoids can be used for applications such as screening drug candidates, toxicity tests, pathophysiological research of diseases, etc.

*5) GeCKO screening method This method can randomly knock out genes by introducing into a cell a diluted mixture of guide RNAs (gRNA) corresponding to all the genes. Thereafter, a cell population having the phenotype of interest is recovered and the knocked out genes responsible for inducing the phenotype of interest can be identified using a next generation sequencer.

*6) Interleukin A bioactive substance produced by immune cells such as lymphocytes, monocytes and macrophages for the regulation of intercellular immune responses. Interleukin 11 and 23 are secreted also from gastric epithelial cells.

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Molecular sleuthing identifies and corrects major flaws in blood-brain barrier model — ScienceDaily

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A type of cell derived from human stem cells that has been widely used for brain research and drug development may have been leading researchers astray for years, according to a study from scientists at Weill Cornell Medicine and Columbia University Irving Medical Center.

The cell, known as an induced Brain Microvascular Endothelial Cell (iBMEC), was first described by other researchers in 2012, and has been used to model the special lining of capillaries in the brain that is called the “blood-brain barrier.” Many brain diseases, including brain cancers as well as degenerative and genetic disorders, could be much more treatable if researchers could get drugs across this barrier. For that and other reasons, iBMEC-based models of the barrier have been embraced as an important standard tool in brain research.

However, in a study published Feb. 4 in the Proceedings of the National Academy of Sciences, the Weill Cornell Medicine scientists, in collaboration with scientists at Columbia University Irving Medical Center and Memorial Sloan Kettering Cancer Center, analyzed the gene expression patterns of iBMECs and found that, in fact, they are not endothelial cells — specialized cells that line blood vessels — and thus are unlikely to be useful in making accurate models of the blood-brain barrier.

“Models of key tissues and structures using stem cell technology are potentially very useful in developing better disease treatments, but as this experience indicates, we need to rigorously evaluate these models before embracing them,” said co-senior author Dr. Raphaël Lis, assistant professor of reproductive medicine in medicine and a member of the Ansary Stem Cell Institute in the Division of Regenerative Medicine at Weill Cornell Medicine. Dr. Lis is also an assistant professor of reproductive medicine in the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medicine.

Since 2007, researchers have known that they can use combinations of transcription factor proteins, which control gene activity, to reprogram ordinary adult cells, such as skin cells sampled from a patient, into cells resembling the stem cells of the embryonic stage of life. Researchers can then use similar reprogramming techniques to coax these cells, called induced pluripotent stem cells, to mature into different cell types — cells that can be studied in the lab for clues to normal health and disease.

The announcement in 2012 that researchers had made iBMECs, using such techniques, was exciting because the cells seemed to be one of the first highly tissue-specific cell types created with stem cell methods. The cells also seemed especially useful for research, for they were thought to be essentially the same as the vessel-lining endothelial cells that form the blood-brain barrier — which normally prevents most molecules in the blood from crossing into brain tissue. Research using iBMECs to model the blood-brain barrier, to better understand neurological diseases and develop new treatments, has been well funded and has expanded to involve many laboratories around the world.

In trying to work with iBMECs, the collaborating teams noted major unexplained discrepancies between these cells and bona fide endothelial cells, for example in their patterns of gene activity. That prompted them to investigate further, using advanced methods including the latest single-cell sequencing techniques, to rigorously compare the gene activity in iBMECs and in authentic human brain endothelial cells.

They found that iBMECs in fact have a largely non-endothelial pattern of gene activity, with little or no activity among key endothelial transcription factors or other accepted gene signatures. The cells, they found, also lack standard cell-surface proteins found in endothelial cells. Their analysis suggested that iBMECs were mistakenly classified as endothelial cells and rather represent different cell type called epithelial cells. Epithelial cells participate in the formation of a physical barrier shielding the body from pathogens and environmental insults, while supporting the transport of fluids, nutrients and waste. Present in numerous organs like intestines, lungs or skin, the epithelial barrier, unlike endothelial cells, is not equipped to transport blood.

The researchers noted that the initial studies of iBMECs almost a decade ago put more emphasis on the mechanical, barrier-like properties of these cells and less on their actual cellular identity as revealed through gene activity patterns.

Generation of various human tissues from pluripotent stem cells is one the most widely used techniques in laboratories world-wide. This study indicates that such techniques should be studied carefully to avoid misidentification of cells that could result in inaccurate outcomes.

“Previously there were fewer methods for studying gene expression profiles, and there was less understanding of the patterns that make up the identities of distinct cell types,” said co-senior author Dr. David Redmond, assistant professor of computational biology research in medicine and a member of the Ansary Stem Cell Institute in the Division of Regenerative Medicine at Weill Cornell Medicine.

The team found that by forcing the activity of three known endothelial cell transcription factors, they could reprogram iBMECs to be much more like endothelial cells.

“We don’t yet have a good ‘blood-brain barrier in a lab dish’ model, but I think we are now a step closer to that goal, and have also corrected an important misconception in the field,” said first author Tyler Lu, a research specialist in the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medicine.

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This cellular mechanism is important for the function of normal blood stem cells — ScienceDaily

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Blood is vital to life, and a healthy body replenishes worn-out blood cells with new ones throughout one’s lifetime. If something goes wrong with this process, serious illness will result.

Researchers from the National University of Singapore (NUS) have now discovered a mechanism controlling the replenishment of blood cells, which could have relevance for new treatments for blood cancers and other blood-related diseases.

The international research team, helmed by Dr Akihiko Numata while he was a Postdoctoral Fellow in the laboratory of Professor Daniel Tenen of the Cancer Science Institute of Singapore and Yong Loo Lin School of Medicine at NUS, focused their investigations on a protein called Tip60, which catalyzes important biological processes in many living organisms. In particular, Tip60 controls hematopoietic stem cells, the source of new blood cells.

In a 10-year-long study, the scientists developed sophisticated molecular tools and experiments to understand the role Tip60 plays in hematopoietic stem cells. They knocked out the protein by modifying its genetic code, thereby deleting certain parts of the protein and preventing it from binding to other biological molecules. The scientists then compared the malfunctioning Tip60 with the normal version.

“We discovered that Tip60 plays a crucial role, activating genes that are in turn responsible for maintaining the hematopoietic stem cells and their DNA. In fact, when completely deprived of Tip60, many of the cells suffered ‘catastrophic’ DNA damage and died. On the other hand, some of the genes that Tip60 affects can lead to leukemia, and understanding this pathway may lead to novel therapeutic approaches,” explained Prof Tenen.

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Two anti-viral enzymes transform pre-leukemia stem cells into leukemia — ScienceDaily

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Since stem cells can continually self-regenerate, making more stem cells, and differentiate into many different specialized cell types, they play an important role in our development and health. But there can also be a dark side — stem cells can sometimes become cancer stem cells, proliferating out of control and leading to blood cancers, such as leukemia and multiple myeloma. The self-renewing nature of cancer stem cells makes them particularly hard to eradicate, and they’re often the reason a blood cancer reoccurs.

Researchers at UC San Diego Health and University of California San Diego School of Medicine are working to understand what pushes pre-cancer stem cells to transform into cancer stem cells and are developing ways to stop that switch.

Their latest study, published January 26, 2021 in Cell Reports, is the first to show that, in response to inflammation, two enzymes called APOBEC3C and ADAR1 work together to fuel the transition from pre-cancer stem cells to cancer stem cells in leukemia. Both APOBEC3C and ADAR1 are activated by inflammatory molecules, especially during the body’s immune response to viruses.

The researchers also found they can prevent the formation of leukemia stem cells in the laboratory by inhibiting ADAR1 with fedratinib or ruxolitinib, two existing medications for myelofibrosis, a rare bone marrow cancer.

“APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy,” said co-senior author Catriona Jamieson, MD, PhD, Koman Family Presidential Endowed Chair in Cancer Research, deputy director of Moores Cancer Center, director of the Sanford Stem Cell Clinical Center and director of the CIRM Alpha Stem Cell Clinic at UC San Diego Health.

Jamieson’s team has long studied ADAR1, an enzyme that edits a cell’s genetic material to control which genes are turned on or off at which times, and its role in leukemia stem cells. They also previously found that high ADAR1 levels correlate with reduced survival rates for patients with multiple myeloma.

In their new study, the researchers collected blood stem cells and saliva samples donated by 54 patients with leukemia and 24 healthy control participants. They compared the whole genome sequences of pre-leukemia stem cells and leukemia stem cells collected from the patients. They were surprised to discover an uptick in levels of both the enzyme APOBEC3C and ADAR1 during the progression to leukemia stem cell. APOBEC3C typically helps cells maintain genomic stability.

The team found that, in response to inflammation, APOBEC3C promotes the proliferation of human pre-leukemia stem cells. That sets the stage for ADAR1, which becomes overzealous in its editing, skewing gene expression in a way that supports leukemia stem cells. When the researchers inhibited ADAR1 activation or silenced the gene in patient cells in the laboratory, they were able to prevent the formation of leukemia stem cells.

APOBEC3C, ADAR1 and their roles in cancer stem cells are now the focus of Jamieson’s NASA-funded project to develop the first dedicated stem cell research laboratory within the International Space Station (ISS).

That’s because the NASA Twins Study — a comprehensive biological comparison of identical twins Scott Kelly, who spent six months aboard the ISS, and Mark Kelly, who stayed on Earth — revealed an increase in inflammatory growth factors, immune dysregulation and pre-cancer mutations in Scott’s blood upon his return. These molecular changes, the perfect conditions to activate APOBEC3C and ADAR1, persisted for almost a year.

“Under the auspices of our NASA task order, we are now developing APOBEC3C and ADAR1 inhibitors as a risk mitigation strategy for astronauts, so we can hopefully predict and prevent pre-cancer stem cell generation in low-Earth orbit and on deep space missions,” Jamieson said.

The team is also interested in further exploring the link between viral infections and cancer. According to Jamieson, infection with viruses can trigger a flood of cytokines, molecules that help stimulate the body’s immune forces. As part of that response, ADAR1 is activated to help immune cells proliferate.

“We need APOBEC3C and ADAR to help us fight off viruses,” she said. “So now we’re wondering — do these enzymes play a role in the immune response to COVID-19? And could there be a downside to that as well? Can the immune response to a viral infection later raise a person’s risk of pre-cancer stem cell development and ultimately cancer stem cell generation, and can we intervene to prevent that?”

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CRISPR technology to cure sickle cell disease — ScienceDaily

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University of Illinois Chicago is one of the U.S. sites participating in clinical trials to cure severe red blood congenital diseases such as sickle cell anemia or Thalassemia by safely modifying the DNA of patients’ blood cells.

The first cases treated with this approach were recently published in an article co-authored by Dr. Damiano Rondelli, the Michael Reese Professor of Hematology at the UIC College of Medicine. The article reports two patients have been cured of beta thalassemia and sickle cell disease after their own genes were edited with CRISPR-Cas9 technology. The two researchers who invented this technology received the Nobel Prize in Chemistry in 2020.

In the paper published in the New England Journal of Medicine, CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia, researchers reported gene editing modified the DNA of stem cells by deleting the gene BCL11A, the gene responsible for suppressing fetal hemoglobin production. By doing so, stem cells start producing fetal hemoglobin so that patients with congenital hemoglobin defects (beta thalassemia or sickle cell disease) make enough fetal hemoglobin to overcome the effect of the defective hemoglobin that causes their disease.

The advantage of this approach is that it uses the patient’s cells with no need for a donor. Also, the gene manipulation does not use a viral vector as with other gene therapy studies but is done with electroporation (quick production of pores into the cells with high voltage) which is known to have low risk of off-target gene activation, according to Rondelli.

Sickle cell disease is an inherited defect of the hemoglobin that causes the red blood cells to become crescent-shaped. These cells can lyse and obstruct small blood vessels, depriving the body’s tissues of oxygen. The disease can cause extreme pain and damage the lungs, heart, kidneys and liver. Beta thalassemia is a blood disorder that reduces the production of hemoglobin — the iron-containing protein in red blood cells that carries oxygen to cells throughout the body. In people with beta thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body.

The first two patients to receive the treatment have had successful results and continue to be monitored. Rondelli is on the steering committee for an international clinical trial, with UIC being the only site in Chicago. Although the trial is at an early stage and the first patients will be followed for some time before expanding the numbers worldwide, UIC will be among the few sites ready for this treatment.

“It is a great privilege for UIC to be part of this international study and I hope that in the future we will have our own patients undergo this procedure,” Rondelli said.

“UIC and UI Health is an ideal place for any cellular therapy in sickle cell disease because of our experience and success in stem cell transplantation in these patients. In fact, over 75% of sickle cell patients can be cured with a transplant, and we have already done over 50 cases,” he said.

While a full-match donor is still the first line of treatment, finding a compatible stem cell donor is challenging. For this reason, many centers including UI health have developed strategies to successfully utilize donors who are only 50% compatible, called haploidentical donors. However, according to Rondelli, in about 30% to 50% of the patients, there are still multiple barriers that can limit the possibility of a donor-derived transplant, such as a family donor availability, or the presence of antibodies in the patient caused by many prior red cell transfusions, that would reject the donor stem cells.

“This gene-editing procedure has the potential to overcome all of these. Cells of the same patient can be manipulated and can be transplanted without the risk of rejection or to cause immune reactions from the donor (graft-versus-host disease),” said Rondelli. “For the almost 900 patients with SC coming to our hospital, this should be great news.”

Patients who in the future will participate in the trial will have cells sent to the CRISPR manufacturing site where the cells undergo genetic editing. Patients then receive chemotherapy prior to the edited stem cells being re-inserted into their bloodstream.

Researchers hope this treatment can be a game-changer for world health. Sickle cell disease and beta thalassemia and other congenital blood disorders are major diseases in the world. Rondelli said 5 million people only in Nigeria suffer from sickle cell disease, and many others in Africa. Also, currently, 30% of transplants being performed in India, which has 1.3 billion people, are to treat severe beta thalassemia, he added.

“The hope is that this treatment will be accessible and affordable in many low-middle-income countries the Middle East, Africa, and India, and have an important impact in the lives of many people in these areas,” said Rondelli.

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Hematopoietic stem cell transplants may provide long-term benefit for people with MS — ScienceDaily

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A new study shows that intense immunosuppression followed by a hematopoietic stem cell transplant may prevent disability associated with multiple sclerosis (MS) from getting worse in 71% of people with relapsing-remitting MS for up to 10 years after the treatment. The research is published in the January 20, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study also found that in some people their disability improved over 10 years after treatment. Additionally, more than half of the people with the secondary progressive form of MS experienced no worsening of their symptoms 10 years after a transplant.

While most people with MS are first diagnosed with relapsing-remitting MS, marked by symptom flare-ups followed by periods of remission, many people with relapsing-remitting MS eventually transition to secondary progressive MS, which does not have wide swings in symptoms but instead a slow, steady worsening of the disease.

The study involved autologous hematopoietic stem cell transplants, which use healthy blood stem cells from the participant’s own body to replace diseased cells.

“So far, conventional treatments have prevented people with MS from experiencing more attacks and worsening symptoms, but not in the long term,” said study author Matilde Inglese, M.D., Ph.D., of the University of Genoa in Italy and a member of the American Academy of Neurology. “Previous research shows more than half of the people with MS who take medication for their disease still get worse over a 10-year period. Our results are exciting because they show hematopoietic stem cell transplants may prevent someone’s MS disabilities from getting worse over the longer term.”

The study looked at 210 people with MS who received stem cell transplants from 1997 to 2019. Their average age was 35. Of those people, 122 had relapsing-remitting MS and 86 had secondary progressive MS and two had primary progressive MS.

Researchers assessed participants at six months, five years and 10 years after their transplants.

Five years into the study, researchers found that 80% of the people experienced no worsening of their MS disability. At the 10-year mark, 66% still had not experienced a worsening of disability.

When looking at just the people with the most common form of MS, researchers found 86% of them experienced no worsening of their disability five years after their transplant. Ten years later, 71% still experienced no worsening of their disability.

Also, people with progressive MS benefited from stem cell transplants. Researchers found that 71% of the people with this type of MS experienced no worsening of their disability five years after their transplants. Ten years later, 57% experienced no worsening of their disability.

“Our study demonstrates that intense immunosuppression followed by hematopoietic stem cell transplants should be considered as a treatment for people with MS, especially those who don’t respond to conventional therapy,” Inglese said.

Limitations of the study include that it was retrospective, did not include a control group and the clinicians who helped measure participants’ disability were aware that they had received stem cell transplants, so that could have led to bias. Inglese said these limitations will be addressed in future research.

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novel stem cell therapy to save the day — ScienceDaily

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In a new study, scientists at Okayama University isolated cardiac stem cells and assessed their potential use as regenerative therapy in young patients with cardiac defects. They confirmed the safety and effectiveness of their proposed treatment in early-phase trials and even identified the mechanism through which the stem cells improved cardiac function. Based on these preliminary findings, they hope to proceed to larger clinical trials and move towards pharmaceutical approval in the future.

Dilated cardiomyopathy (DCM) is a condition caused by the weakening of the heart muscle, affecting the ventricles (chambers in the heart that push blood around the body as it contracts). If allowed to progress unchecked, DCM can lead to heart failure and death, especially in children. The only cure, at present, is a heart transplant, which comes with its own challenges: long waiting times to secure a suitable donor heart, the possibility of organ rejection, long hospitalizations and recovery times, among others.

In recent decades, stem cells have become the cornerstone of regenerative medicine, allowing medical professionals to treat damaged organs and reverse the course of several diseases that were previously deemed irrevocable. Scientists have turned to “cardiosphere-derived cells” (CDCs), a type of cardiac stem cells known to have beneficial effects in adults suffering from specific heart conditions. By developing (“differentiating”) into heart tissue, CDCs can reverse the damage inflicted by diseases. However, little is known about their safety and therapeutic benefit in children.

To address this problem, Professor Hidemasa Oh led an interdepartmental team of scientists at Okayama University, Japan, to launching the first steps to assess this therapy in children suffering from DCM. In a study published in Science Translational Medicine, the team not only showed the effectiveness of CDCs in replenishing damaged tissues in DCM but also revealed how this happens. Prof Oh explains the motivation, “I have been working on cardiac regeneration therapy since 2001. In this study, my team and I assessed the safety and efficacy of using CDCs to treat DCM in children .”

The first step of any trial when testing a new drug or therapy is to use animal models who react similarly to humans, which shows us whether the treatment is safe and has the intended effect. Thus, to begin with, the researchers tested this method in pigs, inducing cardiac symptoms similar to DCM and treating them with different doses of CDCs or a placebo. In those given the stem cell treatment, the scientists noticed quick improvements in cardiac function. The heart muscle thickened, allowing more blood to be pumped around the body. This effectively reversed the damage induced in the pigs’ hearts, an encouraging result leading them to progress to small, controlled human trials.

Their phase 1 trial involved five young patients suffering from DCM. The scientists now had a better idea of the suitable dose of CDCs to give their young patients, thanks to the pre-clinical trials in animals. One year after injection, the patients showed no sign of severe side effects from the treatment, but most importantly, there were encouraging signs of improved heart function. The authors are cautious: based on the small population size of their study, they cannot establish a strong conclusion. However, they are satisfied that CDC treatment appears sufficiently safe and effective to progress to a larger clinical trial. As Prof Oh explains, “We intend to move these results into a randomized phase 2 trial to obtain a pharmaceutical approval of this therapy in Japan .”

Another important finding was the mechanism through which CDCs actually lead to improved cardiac function. Indeed, their analyses revealed that transplanted cells secrete small vesicles called “exosomes,” which are enriched with proteins called “microRNAs” that initiate a whole cascade of molecular interactions. These microRNA-enriched exosomes have two effects. First, it blocks the damage-inducing cells from causing further harm to the heart tissue. Secondly, it induces the differentiation of stem cells into fully functioning cardiac cells (“cardiomyocytes”), starting the regenerative process. This generates hope that injecting these exosomes alone might be enough to reverse this type of heart damage in patients, bypassing the need for CDCs in the first place.

Looking back on their research, the scientists are hopeful that a phase 2 trial will confirm their suspicions, and what this could mean for future patients. Prospective transplant patients sometimes wait for years for a donor heart to become available. This type of therapy could allow them to live relatively normal lives, and even prevent the need for a transplant altogether for patients who have not yet reached such a critical stage.

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Uncovering basic mechanisms of intestinal stem cell self-renewal and differentiation — ScienceDaily

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The gut plays a central role in the regulation of the body’s metabolism and its dysfunction is associated with a variety of diseases, such as obesity, diabetes, colitis and colorectal cancer that affect millions of people worldwide. Targeting endocrine dysfunction at an early stage by stimulating the formation of specific enteroendocrine cells from intestinal stem cells could be a promising regenerative approach for diabetes therapy. For this, however, a detailed understanding of the intestinal stem cell lineage hierarchy and the signals regulating the recruitment of the different intestinal cell types is critical.

Heiko Lickert and his research group have taken up this challenge. Lickert is director of the Institute of Diabetes and Regeneration Research at Helmholtz Zentrum München, professor of beta cell biology at Technical University of Munich (TUM) and member of the German Center for Diabetes Research (DZD). In the following, Lickert and first author Anika Böttcher talk about their latest paper on the basic mechanisms of intestinal stem cell function published in Nature Cell Biology.

Why is the gut so important for health research?

Heiko Lickert: As the body’s digestive and largest endocrine system, the gut is central to the regulation of energy and glucose homeostasis. Intestinal functions are carried out by specialized cells which are constantly generated and renewed every 3-4 days from intestinal stem cells. For example, so-called enteroendocrine cells produce over 20 different types of hormones that signal to the brain and pancreas to regulate for instance appetite, food intake, gastric emptying and insulin secretion from pancreatic beta cells. Another important gut function is exerted by so-called Paneth cells that produce defensins and protect against invading pathogens. Consequently, it is not surprising that intestinal dysfunction is associated with a variety of diseases, such as chronic inflammation,colorectal cancer and diabetes, affecting millions of people worldwide.

What were the most important findings in your latest research about intestinal stem cells?

Anika Böttcher: We improved our understanding of how intestinal stem cells constantly renew and give rise to specialized cell types at unprecedented single cell resolution. Thus, we are now able to describe potential progenitor populations for each intestinal cell and we have shown that for every lineage intestinal stem cells give rise to unipotent lineage progenitors. Furthermore, we identified a specific intestinal stem cell niche signal pathway (called Wnt/planar cell polarity pathway) regulating intestinal stem cell self-renewal and lineage decisions. This is very important, as we know that intestinal stem cells can indefinitely renew and maintain the gut function and tissue barrier. Those are 6 meters of epithelium and more than 100 million of cells generated every day in humans! Moreover, these cells differentiate into every single cell type. The risk of failure in this self-renewal or lineage specification process to result in a chronic disease therefore is quite high.

Using a more technical term, we were able to delineate a detailed intestinal stem cell lineage tree and identified new niche signals. In order to obtain those breaking-through results, we integrated time-resolved lineage labelling of rare intestinal lineages using different reporter mouse lines with genome-wide and targeted single-cell gene expression analysis to dissect intestinal stem cell lineage decisions. Together with Fabian Theis’ team of computational biologists at Helmholtz Munich and TUM, we profiled 60,000 intestinal cells. To analyze this data set, we leveraged newly developed machine learning techniques to automatically identify branching lineages and key contributing factors in the gene expression space. The findings are broadly applicable and are equally important for cancer, inflammation and colitis as well as obesity and diabetes.

How can this new knowledge be translated to therapeutic approaches?

Heiko Lickert: This study challenges current paradigms and we advanced our understanding of intestinal stem cell self-renewal, heterogeneity and lineage recruitment. We can use this basic knowledge to map what happens to intestinal stem cell lineage allocation and differentiation during chronic disease. Insights from this will put us in place to develop specific therapies for these diseases by targeting lineage progenitors for example to regenerate the formation of specific cells that are lost during disease progression or to identify and eradicate intestinal cancer stem cells. Specifically, at our institute, we will focus our efforts on diabetes.

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