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March 2020

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Development could lead to better disease models in the lab to test treatments for efficacy — ScienceDaily

Boston researchers have developed a new way to generate groups of intestinal cells that can be used, among others, to make disease models in the lab to test treatments for diseases affecting the gastrointestinal system. Using human induced pluripotent stem cells, this novel approach combined a variety of techniques that enabled the development of three-dimensional groups of intestinal cells called organoids in vitro, which can expand disease treatment testing in the lab using human cells.

Published online in Nature Communications, this process provides a novel platform to improve drug screenings and uncover novel therapies to treat a variety of diseases impacting the intestine, such as inflammatory bowel disease, colon cancer and Cystic Fibrosis.

Researchers at the Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center used donated human induced pluripotent stem cells (hiPSCs), which are created by reprogramming adult cells into a primitive state. For this study, these cells were pushed to differentiate into intestinal cells using specific growth factors in order to create organoids in a gel. This new protocol allowed the cells to develop without mesenchyme, which typically in other protocols, provides support for the intestinal epithelial cells to grow. By taking out the mesenchyme, the researchers could study exclusively epithelial cells, which make up the intestinal tract.

In addition, using CRISPR technology, the researchers were able to modify and create a novel iPSC stem cell line that glowed green when differentiated into intestinal cells. This allowed the researchers to follow the process of how intestinal cells differentiate in vitro.

“Generating organoids in our lab allows us to create more accurate disease models, which are used to test treatments and therapies targeted to a specific genetic defect or tissue — and it’s all possible without harming the patient,” said Gustavo Mostoslavsky, MD, PhD, co-director of CReM and faculty in the gastroenterology section at Boston Medical Center. “This approach allows us to determine what treatments could be most effective, and which are ineffective, against a disease.”

Using this new protocol, the researchers generated intestinal organoids from iPSCs containing a mutation that causes Cystic Fibrosis, which typically affects several organs, including the gastrointestinal tract. Using CRISPR technology, the researchers corrected the mutation in the intestinal organoids. The intestinal organoids with the mutation did not respond to a drug while the genetically corrected cells did respond, demonstrating their future potential for disease modeling and therapeutic screening applications.

The protocol developed in this study provides strong evidence to continue using human iPSCs to study development at the cellular level, tissue engineering and disease modeling in order to advance the understanding — and possibilities — of regenerative medicine.

“I hope that this study helps move forward our collective understanding about how diseases impact the gastrointestinal tract at the cellular level,” said Mostoslavsky, who also is associate professor of medicine and microbiology at Boston University School of Medicine. “The continual development of novel techniques in creating highly differentiated cells that can be used to develop disease models in a lab setting will pave the way for the development of more targeted approaches to treat many different diseases.”

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Blood stem cells boost immunity by keeping a record of previous infections — ScienceDaily

These findings should have a significant impact on future vaccination strategies and pave the way for new treatments of an underperforming or over-reacting immune system. The results of this research are published in Cell Stem Cell on March 12, 2020.

Stem cells in our bodies act as reservoirs of cells that divide to produce new stem cells, as well as a myriad of different types of specialized cells, required to secure tissue renewal and function. Commonly called “blood stem cells,” the hematopoietic stem cells (HSC) are nestled in the bone marrow, the soft tissue that is in the center of large bones such as the hips or thighs. Their role is to renew the repertoire of blood cells, including cells of the immune system which are crucial to fight infections and other diseases.

Until a decade ago, the dogma was that HSCs were unspecialized cells, blind to external signals such as infections. Only their specialized daughter cells would sense these signals and activate an immune response. But work from Prof. Michael Sieweke’s laboratory and others over the past years has proven this dogma wrong and shown that HSCs can actually sense external factors to specifically produce subtypes of immune cells “on demand” to fight an infection. Beyond their role in an emergency immune response, the question remained as to the function of HSCs in responding to repeated infectious episodes. The immune system is known to have a memory that allows it to better respond to returning infectious agents. The present study now establishes a central role for blood stem cells in this memory.

“We discovered that HSCs could drive a more rapid and efficient immune response if they had previously been exposed to LPS, a bacterial molecule that mimics infection,” said Dr. Sandrine Sarrazin, Inserm researcher and senior-author of the publication. Prof. Michael Sieweke, Humboldt Professor at TU Dresden, CNRS Research Director and last author of the publication, explained how they found the memory was stored within the cells: “The first exposure to LPS causes marks to be deposited on the DNA of the stem cells, right around genes that are important for an immune response. Much like bookmarks, the marks on the DNA ensure that these genes are easily found, accessible and activated for a rapid response if a second infection by a similar agent was to come.”

The authors further explored how the memory was inscribed on the DNA, and found C/EBP? to be the major actor, describing a new function for this factor, which is also important for emergency immune responses. Together, these findings should lead to improvements in tuning the immune system or better vaccination strategies.

“The ability of the immune system to keep track of previous infections and respond more efficiently the second time they are encountered is the founding principle of vaccines. Now that we understand how blood stem cells book mark immune response circuits, we should be able to optimize immunization strategies to broaden the protection to infectious agents. It could also more generally lead to new ways to boost the immune response when it underperforms or turn it off when it overreacts,” concluded Prof. Michael Sieweke.

The research group of Prof. Michael Sieweke works at the interface of immunology and stem cell research. The scientists focus on the study of hematopoietic stem cells and macrophages, long-lived mature cells of the immune system that fulfil an important role in tissue regeneration. In 2018, Prof. Michael Sieweke received the most valuable research award in Germany: the Alexander von Humboldt Professorship, which brings top international researchers to German universities. In addition to his position as Research Director at the Centre for Immunology at the University of Marseille Luminy, he now acts as Deputy Director at the Center for Regenerative Therapies at TU Dresden (CRTD). CRTD is 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, hematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases.

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New technique ‘prints’ cells to create diverse biological environments — ScienceDaily

Like humans, cells can be easily influenced by peer pressure.

Take a neural stem cell in the brain: Whether this cell remains a stem cell or differentiates into a fully formed brain cell is ultimately determined by a complex set of molecular messages the cell receives from countless neighbors. Understanding these messages is key for scientists hoping to harness these stem cells to treat neurological conditions like Alzheimer’s or Parkinson’s.

With the help of photolithography and a creative use of programmable DNA, University of California, Berkeley, researchers have created a new technique that can rapidly “print” two-dimensional arrays of cells and proteins that mimic a wide variety of cellular environments in the body — be it the brain tissue surrounding a neural stem cell, the lining of the intestine or liver or the cellular configuration inside a tumor.

This technique could help scientists develop a better understanding of the complex cell-to-cell messaging that dictates a cell’s final fate, from neural stem cell differentiating into a brain cell to a tumor cell with the potential to metastasize to an embryonic stem cell becoming an organ cell.

“What’s really powerful about this platform is you can create in vitro tissues that capture the spatial organization of cells in the body, from the intestinal lining of your digestive tract to the arrangements of different cell types in the liver,” said Olivia Scheideler, who completed the research as a graduate student at Berkeley. “I think you could apply this technique to recreate any tissue where you want to explore how cellular interactions contribute to tissue function.”

In a paper appearing today (Wednesday, March 18) in the journal Science Advances, Scheideler and her collaborators show that the new technique can be used to rapidly print intricate patterns of up to 10 different kinds cells or proteins onto a flat surface.

“Essentially, what this technique allows us to do is pattern different kinds of conditions in one shot and in a high-throughput manner,” said Lydia Sohn, Chancellor’s Professor of Mechanical Engineering at UC Berkeley and senior author of the paper. “It provides a whole range of options for what you could study, because it’s so flexible. You can pattern many different kinds of cells or proteins.”

Caught on a DNA tether

In the new technique, each cell or protein is tethered to a substrate with a short string of DNA. While similar methods have been developed that attach tethered cells or proteins one by one, the new technique takes advantage of a patterning process called photolithography to attach, or print, each type of cell protein in one quick batch, greatly speeding up the process.

“It’s like color laser printing, where you print one color and then print another,” Sohn said.

Like photography, photolithography works by exposing a coated surface or substrate to a pattern of light, which initiates a chemical reaction that dissolves the coating in the illuminated areas, leaving a templated substrate. In the new technique, the substrate is then bathed in strands of single-sided DNA, whose ends have been chemically altered to firmly latch on where the coating has been dissolved.

Each single-sided DNA strand is programmed have a specific sequence of the nucleotides adenine (A), thymine (T), guanine (G) and cytosine (C). Single-sided DNA strands with the complementary nucleotide sequence are embedded or attached to cells or proteins of interest.

Finally, the surface is washed with a mixture of cells or proteins attached to the complementary strands of single-sided DNA, which bond with the single-sided DNA already attached to the surface to form double-helix “tethers.”

“All the cells and proteins attach exactly where they should be because of the DNA programming,” Sohn said.

By repeating the process, up to 10 different kinds of cells or proteins can be tethered to the surface in an arbitrary pattern.

Conflicting messages

To demonstrate one of the many applications of the technique, Scheideler and co-author David Schaffer, Hubbard Howe Jr. Distinguished Professor of Biochemical Engineering at UC Berkeley, used the platform to study the chemical signaling that cues neural stem cells to differentiate into mature cells.

“Stem cells have programs embedded inside their DNA that tell them (to) either stay a stem cell or to differentiate into a mature cell,'” Schaffer said. “And they receive a lot of information about what to do and which programs to activate from the environment, from other cells around them. If we could learn how to make stem cells do our bidding, how to turn them into a particular cell type, then we could harness the stem cells to mass produce specialized cell types that were lost due to disease or injury.”

Neural stem cells in the brain regularly receive conflicting messages from their neighbors about how they should behave, Scheideler said. One messenger, the FGF-2 protein, tells them to make more stem cells. The other, the ephrin-B2 protein, tells them to differentiate into a mature neuron.

Scheideler used the new technique to pattern neural stem cells onto thousands of different arrays of the two proteins, FGF-2 and ephrin-B2, to see how the spatial organization of the two signals helps determine the cells’ ultimate fate.

She found that many stem cells differentiated into mature neurons, even when they were primarily in contact with FGF-2, or “stay a stem cell,” messengers. When she looked closer, however, she found that those cells that differentiated were more likely to have small, finger-like extensions, or “neurites,” that touched the ephrin-B2 or “differentiate” messengers.

“The great thing about this patterning technology is you can easily replicate these little patterns hundreds or thousands of times across a slide,” Schaffer said. “It is like running a thousand little independent experiments, each of which is a trial run to see how a stem cell listens to the cells around it. And then you can get very, very deep statistics about the various ways that it can be regulated.”

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First genomic study of puberty yields insights into development and cancer — ScienceDaily

In the first-ever genome-scale analysis of the puberty process in humans, researchers at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) outline distinct and critical changes to stem cells in males during adolescence. They further outline how testosterone, and the cells that produce testosterone, impact stem cells in male reproductive organs. The researchers believe this study adds dramatically to a foundation of knowledge that may yield insights into critical areas of human health, including infertility and cellular changes that lead to cancer and other diseases.

The study, published today in the journal Cell Stem Cell, was led by Bradley Cairns, PhD, cancer researcher at HCI and professor and chair of oncological sciences at the U of U, in collaboration with colleagues Jingtao Guo, PhD, a postdoctoral fellow in the Cairns lab at HCI, James Hotaling, MD, associate professor of surgery at the U of U, and Anne Goriely, PhD, associate professor of human genetics at the University of Oxford.

Puberty spurs numerous developmental changes in humans and other mammals. Hallmarks of puberty include physical characteristics easily visible to the naked eye, like rapid growth. These physical and hormonal changes signal the process of a maturing body preparing for reproductive years.

In the testis, the male reproductive organ that makes and stores sperm and produces testosterone, puberty introduces monumental changes at a cellular and physiological level. Thanks to new genomic technologies, researchers are able to examine the expression of thousands of genes in each individual cell in an entire organ, providing unprecedented insights into cellular behavior during puberty.

Several types of cells within the testis regulate reproductive health. Like the human body that changes along the path from infancy to adulthood, these cells undergo major changes as the body matures. These cells include spermatogonial stem cells that ultimately generate sperm production, and niche cells that help form parts of the testis, such as the seminiferous tubule, a tube-like structure within which sperm is formed. In this study, researchers characterized how, just prior to puberty, spermatogonial stem cells first expand significantly in number. These stem cells progress toward meiosis, a special type of cell division that splits the number of chromosomes from the parent cell in half, and also separates the male X and Y sex chromosomes to create cells that, after fertilization of eggs and considerable subsequent development, will ultimately result in either male (Y-containing) or female (X-containing) children. Late in puberty, these stem cells commit to creating mature sperm, which includes a tail piece for motility. The researchers showed how two of the cells that form the stem cell niche and chaperone this process — the myoid cells and Leydig cells — derive from a common precursor, and mature during early puberty.

A major novel insight of this study was the first-ever genomic analysis of the testis of adult transfemales (individuals assigned male at birth, but who self-identify as female). For these individuals, gender confirmation surgery is preceded by hormone therapy that induces long-term testosterone suppression, enabling the examination of testis lacking testosterone. By using samples donated after surgery, researchers uncovered critical insights into the role of testosterone in maintaining testis development. Genomic analysis of the cells from the testis of transfemales showed that stem cells and other cells revert to earlier states of development when compared to samples from male adolescents. Thus, Cairns and his colleagues identified that testosterone is critical to maintaining the mature state of the testis: if testosterone is no longer present, the testis reverts to an earlier developmental state.

The major changes that occur in humans during puberty give rise to numerous functions in normal development, like reproductive health and fertility. But, when these processes go awry, confounding challenges can result. Infertility is a relatively common health issue. About 50 percent of the time, the underlying cause is attributed to the male reproductive functions, which often include errors that occur during puberty. The team hopes these insights into how cells develop will help yield insights into what happens when developmental issues during puberty cause changes that result in infertility.

The study also informs understanding of cancer and other diseases that arise due to errors in cellular processes. “The majority of the time, testicular cancers arise when stem cells in the testis are misregulated,” said Cairns. “We want to understand how these changes can cause testicular tumors; however, we need to know what should normally happen before we can identify ways to prevent or more effectively treat these cancers.”

In juveniles, cancers and reproductive health intersect via a medical process called oncofertility; that is, the study of how to retain fertility in adolescent and young adult cancer patients whose reproductive health and fertility may be impacted by their cancer, or as a result of side effects of cancer treatment. “Some chemotherapies can result in young men with cancer not being able to have children — the chemotherapy can cause changes to their stem cells,” said Cairns. “My hope and expectation is that our research will provide a foundation for creating options to support the reproductive health of young men affected by cancer through a better understanding of how these stem cells survive, are supported, and develop.”

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Programmable biomaterials for bone regeneration introduced — ScienceDaily

Specifically programmed materials can, under specific conditions, encourage stem cells to transform into bone cells. To do this, scientists implemented a so-called shape-memory polymer in stem cell research.

Stem cells are known for their ability to turn into many different types of cell, be they muscle cells, cartilage, or bone cells. Just like the body they are part of, stem cells sense what happens around them and react accordingly. For decades, researchers have been learning how to steer this differentiation process by changing the cells’ environment. The knowledge acquired is already being used in tissue engineering, in other words, to generate substitute materials that restore or maintain damaged biological tissues. However, most research has been done on static scaffolds. Now, researchers from the Helmholtz-Zentrum Geesthacht (HZG), the Berlin-Brandenburg Centre for Regenerative Therapies, the Freien Universität Berlin and the Helmholtz Virtual Institute for Multifunctional Biomaterials in medicine have used a dynamic scaffold.

New method created

The researchers took a polymer sheet that acts like an artificial muscle. The sheet has the unusual property in that it is trained to reversibly morph when exposed to repeated temperature changes. The researchers simply moulded a grid onto the underside of the sheet and programmed it to stretch as the temperature went from body temperature (37 °C) to 10 °C and to contract when re-heated. They then seeded the sheet with stem cells, and carefully observed the changing shape of the gridded sheet and cells. With the help of this “artificial muscle,” the scientists could use one physical signal — the temperature change — to simultaneously send a second mechanical signal to the stem cells. With these synchronised stimuli it is possible to encourage the stem cells to turn themselves into bone cells.

“Our polymer actuator sheet has a so-called shape-memory function. In our experiments, this allows it to act like a transducer, with which we can effectively instruct the cells to do as we wish. We found that the changes in temperature, combined with the repeated stretching motion of the film was enough to encourage the stem cells to differentiate into bone cells” explained Professor Andreas Lendlein an author of the paper and head of the HZG’s Institute of Biomaterial Science in Teltow, Germany.

Potential application in complex bone fractures

“The programmed polymer sheets could, for example, later be used to treat bones broken so severely that the body can’t repair it by itself. Stem cells from a patient’s bone marrow could be cultured on the sheet and adaptively wrap around the bone during an operation. The previously “trained” cells could then directly strengthen the bones,” said Professor Lendlein.

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Heart problems, graft-versus-host disease are concerns — ScienceDaily

A stem cell transplant — also called a bone marrow transplant — is a common treatment for blood cancers, such as acute myeloid leukemia (AML). Such treatment can cure blood cancers but also can lead to life-threatening complications, including heart problems and graft-versus-host disease, in which new immune cells from the donor attack a patient’s healthy tissues.

A new study from Washington University School of Medicine in St. Louis suggests that extremely rare, harmful genetic mutations present in healthy donors’ stem cells — though not causing health problems in the donors — may be passed on to cancer patients receiving stem cell transplants. The intense chemo- and radiation therapy prior to transplant and the immunosuppression given after allow cells with these rare mutations the opportunity to quickly replicate, potentially creating health problems for the patients who receive them, suggests the research, published Jan. 15 in the journal Science Translational Medicine.

Among the concerns are heart damage, graft-versus-host disease and possible new leukemias.

The study, involving samples from patients with AML and their stem cell donors, suggests such rare, harmful mutations are present in surprisingly young donors and can cause problems for recipients even if the mutations are so rare as to be undetectable in the donor by typical genome sequencing techniques. The research opens the door to a larger study that will investigate these rare mutations in many more healthy donors, potentially leading to ways to prevent or mitigate the health effects of such genetic errors in patients receiving stem cell transplants.

“There have been suspicions that genetic errors in donor stem cells may be causing problems in cancer patients, but until now we didn’t have a way to identify them because they are so rare,” said senior author Todd E. Druley, MD, PhD, an associate professor of pediatrics. “This study raises concerns that even young, healthy donors’ blood stem cells may have harmful mutations and provides strong evidence that we need to explore the potential effects of these mutations further.”

Added co-author Sima T. Bhatt, MD, an assistant professor of pediatrics who treats pediatric patients with blood cancers at Siteman Kids at St. Louis Children’s Hospital and Washington University School of Medicine: “Transplant physicians tend to seek younger donors because we assume this will lead to fewer complications. But we now see evidence that even young and healthy donors can have mutations that will have consequences for our patients. We need to understand what those consequences are if we are to find ways to modify them.”

The study analyzed bone marrow from 25 adult patients with AML whose samples had been stored in a repository at Washington University. Samples from their healthy matched donors, who were unrelated to the patients, also were sequenced. The donors’ samples were provided by the Center for International Blood and Marrow Transplant Research in Milwaukee.

The 25 AML patients were chosen because they each had had samples banked at four separate times: before the transplant, at 30 days post-transplant, at 100 days post-transplant, and one year post-transplant.

Druley co-invented a technique called error-corrected sequencing, to identify extremely rare DNA mutations that would be missed by conventional genome sequencing. Typical next-generation sequencing techniques can correctly identify a mutation that is present in one in 100 cells. The new method, which can distinguish between true mutations and mistakes introduced by the sequencing machine, allows the researchers to find true mutations that are extremely rare — those present in as few as one in 10,000 cells.

The healthy donors ranged in age from 20 to 58, with an average age of 26. The researchers sequenced 80 genes known to be associated with AML, and they identified at least one harmful genetic mutation in 11 of the 25 donors, or 44%. They further showed that 84% of all the various mutations identified in the donors’ samples were potentially harmful, and that 100% of the harmful mutations present in the donors later were found in the recipients. These harmful mutations also persisted over time, and many increased in frequency. Such data suggest the harmful mutations from the donor confer a survival advantage to the cells that harbor them.

“We didn’t expect this many young, healthy donors to have these types of mutations,” Druley said. “We also didn’t expect 100% of the harmful mutations to be engrafted into the recipients. That was striking.”

According to the researchers, the study raises questions about the origins of some of the well-known side effects of stem cell transplantation.

“We see a trend between mutations from the donor that persist over time and the development of chronic graft-versus-host disease,” said first author Wing Hing Wong, a doctoral student in Druley’s lab. “We plan to examine this more closely in a larger study.”

Though the study was not large enough to establish a causal link, the researchers found that 75% of the patients who received at least one harmful mutation in the 80 genes that persisted over time developed chronic graft-versus-host disease. Among patients who did not receive mutations in the 80 genes, about 50% developed the condition. Because the study was small, this difference was not statistically significant, but it is evidence that the association should be studied more closely. In general, about half of all patients who receive a stem cell transplant go on to develop some form of graft-versus-host disease.

The most common mutation seen in the donors and the cancer patients studied is in a gene associated with heart disease. Healthy people with mutations in this gene are at higher risk of heart attack due to plaque buildup in the arteries.

“We know that cardiac dysfunction is a major complication after a bone marrow transplant, but it’s always been attributed to toxicity from radiation or chemotherapy,” Druley said. “It’s never been linked to mutations in the blood-forming cells. We can’t make this claim definitively, but we have data to suggest we should study that in much more detail.”

Added Bhatt: “Now that we’ve also linked these mutations to graft-versus-host disease and cardiovascular problems, we have a larger study planned that we hope will answer some of the questions posed by this one.”

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Producing human tissue in space — ScienceDaily

On 6 March at 11:50 PM EST, the International Space Station resupply mission Space X CRS-20 took off from Cape Canaveral (USA). On board: 250 test tubes from the University of Zurich containing adult human stem cells. These stem cells will develop into bone, cartilage and other organs during the month-long stay in space. Professor Oliver Ullrich and Dr. Cora Thiel, the two research leaders at the UZH Space Hub, are testing their innovative concept of human tissue production in weightlessness for the benefit of transplantation medicine and precision medicine and as an alternative to animal experiments.

Weightlessness as a tool

“We are using weightlessness as a tool,” explains Cora Thiel. Physical forces such as gravity influence how stem cells differentiate and how the formation and regeneration of tissue is organized. The researchers assume that due to the low gravity on board the ISS, newly formed cells organize themselves into three-dimensional tissues without an additional matrix or other auxiliary structures. The experiment will take place in a mobile mini-laboratory, the CubeLab module of the US company Space Tango. The module consists of a closed and sterile system, in which the stem cells can proliferate and differentiate at constant temperature.

If the test project is successful, it is planned to gradually switch from a small laboratory to a larger production scale. In the future, the innovative process can be used to generate tissue transplants such as cartilage or new liver cells in space from stem cells which are harvested from individual patients in a routine procedure. According to Oliver Ullrich, an additional application is emerging in precision medicine: “Artificially produced autologous human tissue could be used to determine which combination of drugs is the most suitable for the patient in question. In addition, human tissue and organ-like structures produced in space could help to reduce the number of animal experiments.”

Public-private partnership between university and industry

Airbus is also convinced of the potential. The public-private partnership is structured as follows: The Airbus division “Defence and Space” has designed the inlets for the interior of the transport boxes. For their design and manufacture, innovative processes such as selective laser sintering (SLS), a special 3D printing process, were used. The inlets ensure safe transport of the cell samples with maximum volume utilization. In addition, Airbus is organizing access to the ISS, transport of the test tubes to and from the ISS and providing ground support equipment. Ullrich and Thiel are contributing the research idea and study design, and are carrying out the scientific work and providing the scientific staff.

Low Earth Orbit as a future research, development and production location

Contrary to widespread opinion, transportation into space no longer causes costs to skyrocket today. “In space projects, the main cost drivers are the custom-made hardware and the bureaucracy,” says Ullrich, Professor of Anatomy at UZH and director of the UZH Space Hub. He therefore deliberately relies on established medical serial products for equipment and instruments. Ullrich is convinced of the future benefits of space flight: “In a few decades, humankind will use the low Earth orbit as a routine place for research, development and production.”

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How stem cells repair damage from heart attacks — ScienceDaily

Mayo Clinic researchers have uncovered stem cell-activated mechanisms of healing after a heart attack. Stem cells restored cardiac muscle back to its condition before the heart attack, in turn providing a blueprint of how stem cells may work.

The study, published in NPJ Regenerative Medicine, finds that human cardiopoietic cells zero in on damaged proteins to reverse complex changes caused by a heart attack. Cardiopoietic cells are derived from adult stem cell sources of bone marrow.

“The extent of change caused by a heart attack is too great for the heart to repair itself or to prevent further damage from occurring. Notably, however, cardiopoietic stem cell therapy reversed, either fully or partially, two-thirds of these disease-induced changes, such that 85% of all cellular functional categories affected by disease responded favorably to treatment,” says Andre Terzic, M.D., Ph.D., director of Mayo Clinic’s Center for Regenerative Medicine. Dr. Terzic is the senior author of the study.

This new understanding of how stem cells restore heart health could provide the framework for broader applications of stem cell therapy across various conditions.

“The actual mode of action of stem cells in repairing a diseased organ has until now been poorly understood, limiting adoption in clinical care. This study sheds light on the most intimate, yet comprehensive, regenerative mechanisms ? paving a road map for responsible and increasingly informed stem cell application,” says Dr. Terzic.

Heart disease is a leading cause of death in the U.S. Every 40 seconds, someone in the U.S. has a heart attack, according to the Centers for Disease Control and Prevention. During a heart attack, cardiac tissue dies, weakening the heart.

“The response of the diseased heart to cardiopoietic stem cell treatment revealed development and growth of new blood vessels, along with new heart tissue,” adds Kent Arrell, Ph.D., a Mayo Clinic cardiovascular researcher and first author of the study.

The research

Researchers compared the diseased hearts of mice that did not receive human cardiopoietic stem cell therapy with those that did. Using a data science approach to map all the proteins in the heart muscle, researchers identified 4,000 cardiac proteins, more than 10% of which suffered damage by a heart attack.

“While we anticipated that the stem cell treatment would produce a beneficial outcome, we were surprised how far it shifted the state of diseased hearts away from disease and back toward a healthy, pre-disease state,” says Dr. Arrell.

Cardiopoietic stem cells are being tested in advanced clinical trials in heart patients.

“The current findings will enrich the base of knowledge pertinent to stem cell therapies and may have the potential to guide therapeutic regimens in the future,” says Dr. Terzic.

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Materials provided by Mayo Clinic. Original written by Susan Buckles. Note: Content may be edited for style and length.

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Long-term follow-up of the London patient suggests no detectable active HIV virus remains in the patient — ScienceDaily

A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient’s blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Although there was no active viral infection in the patient’s body, remnants of integrated HIV-1 DNA remained in tissue samples, which were also found in the first patient to be cured of HIV. The authors suggest that these can be regarded as so-called ‘fossils’, as they are unlikely to be capable of reproducing the virus.

Lead author on the study, Professor Ravindra Kumar Gupta, University of Cambridge, UK, says: “We propose that these results represent the second ever case of a patient to be cured of HIV. Our findings show that the success of stem cell transplantation as a cure for HIV, first reported nine years ago in the Berlin patient, can be replicated.”

He cautions: “It is important to note that this curative treatment is high-risk, and only used as a last resort for patients with HIV who also have life-threatening haematological malignancies. Therefore, this is not a treatment that would be offered widely to patients with HIV who are on successful antiretroviral treatment. 

While most HIV patients can manage the virus with current treatment options and have the possibility of living a long and healthy life, experimental research of this kind following patients who have undergone high-risk, last-resort curative treatments, can provide insight into how a more widely applicable cure might be developed in the future.

In 2011, another patient based in Berlin (the ‘Berlin patient’) was the first HIV patient to be reported cured of the virus three and half years after undergoing similar treatment. Their treatment included total body irradiation, two rounds of stem cell transplant from a donor who carried a gene (CCR5?32/?32) that is resistant to HIV, and a chemotherapy drug regimen. The transplant aims to make the virus unable to replicate in the patient’s body by replacing the patient’s immune cells with those of the donors, whilst the body irradiation and chemotherapy targets any residual HIV virus.

The patient reported in this study (the ‘London patient’), underwent one stem-cell transplantation, a reduced-intensity chemotherapy drug regimen, without whole body irradiation. In 2019, it was reported that their HIV was in remission, and this study provides follow-up viral load blood test results at 30-months and a modelling analysis to predict the chances of viral re-emergence.

Ultrasensitive viral load sampling from the London patient’s cerebrospinal fluid, intestinal tissue, or lymphoid tissue was taken at 29 months after interruption of ART and viral load sampling of their blood at 30 months. At 29 months, CD4 cell count (indicators of immune system health and stem cell transplantation success) was measured, and the extent to which the patient’s immune cells have been replaced by those derived from the transplant.

Results showed no active viral infection was detected in samples of the patient’s blood at 30 months, or in their cerebrospinal fluid, semen, intestinal tissue, and lymphoid tissue 29 months after stopping ART.

The patient had a healthy CD4 cell count, suggesting they have recovered well from the transplant, with their CD4 cells replaced by cells derived from the HIV-resistant transplanted stem cells.

Furthermore, 99% of the patient’s immune cells were derived from the donor’s stem cells, indicating the stem-cell transplant had been successful.

Since it was not possible to measure proportion of cells derived from the donor’s stem cells in all parts of the patient’s body (i.e. measurement was not possible in some tissue cells like lymph nodes), the authors used a modelling analysis to predict the probability of cure based on two possible scenarios. If 80% of patient’s cells are derived from the transplant, the probability of cure is predicted at 98%; whereas if they have 90% donor derived cells, they predict a 99% probability of cure.

Comparing to the treatment used on the Berlin patient, the authors highlight that their case study of the London patient represents a step towards a less intensive treatment approach, showing that the long-term remission of HIV can be achieved using reduced intensity drug regimens, with one stem cell transplant (rather than two) and without total body irradiation.

However, being only the second reported patient to undergo this experimental treatment successfully, the authors note that that the London patient will need continued, but much less frequent, monitoring for re-emergence of the virus.

Speculating on what their results might mean for future developments of HIV cures that utilise the CCR5 (HIV resistant) gene, co-author on the study, Dr Dimitra Peppa, University of Oxford, UK, says: “Gene editing using the CCR5 has received a lot of attention recently. The London and Berlin patient are examples of using the CCR5 gene in curative therapies outside of gene editing. There are still many ethical and technical barriers — e.g. gene editing, efficiency and robust safety data — to overcome before any approach using CCR5 gene editing can be considered as a scalable cure strategy for HIV.”

Writing in a linked Comment, lead author Professor Sharon R Lewin, University of Melbourne, Australia, (who was not involved in the study), says, “The finding of no intact virus can be reassuring for a patient who might face significant anxiety and uncertainty about whether and when viral rebound off ART might occur, which in other settings has been completely unpredictable. Given the large number of cells sampled here and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow up case report is certainly encouraging but unfortunately in the end, only time will tell.”

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Early studies show further applications that could impact donor transplant system — ScienceDaily

A team of researchers at the University of Minnesota Medical School recently proved the ability to grow human-derived blood vessels in a pig — a novel approach that has the potential for providing unlimited human vessels for transplant purposes. Because these vessels were made with patient-derived skin cells, they are less likely to be rejected by the recipient, helping patients potentially avoid the need for life-long, anti-rejection drugs.

Daniel Garry, MD, PhD, and Mary Garry, PhD, both professors in the Department of Medicine at the U of M Medical School, co-led the research team and published their findings in Nature Biotechnology last week.

“There’s so many chronic and terminal diseases, and many people are not able to participate in organ transplantation,” said Daniel, who is also a heart failure and transplant cardiologist. “About 98 percent of people are not going to be eligible for a heart transplant, so there’s been a huge effort in trying to come up with strategies to increase the donor pool. Our approach looked at a pig.”

Because of similarities between human and pig physiology, scientists have historically studied pigs to discover treatments for health issues, including diabetes. Before researchers engineered human insulin, doctors treated patients with pig insulin.

“Our discovery has made a platform for making human blood vessels in a pig,” said Daniel. “This could allow us to make organs with human blood vessels that would be less apt to be rejected and could be used in patients in need of a transplant. That’s what typically causes rejection — the lining of the blood vessels in the organs.”

The blood vessels created by the Garry duo will avoid rejection because of the method by which they are made. The team injects human-induced pluripotent stem cells — taken from mature cells scraped from a patient’s skin and reprogrammed to a stem cell state — into a pig embryo, which is then placed into a surrogate pig. In the future, viable piglets, with blood vessels that will be an exact match to the patient, will ensure a successful transplant and the ability to live without the need for immunosuppression, or anti-rejection, drugs.

“There’s hundreds of thousands of patients that have peripheral artery disease, either because of smoking or diabetes or any number of causes, and they have limb amputations,” Mary said. “These blood vessels would be engineered and could be utilized in these patients to prevent those kinds of life-long handicaps, if you will.”

The first phase of their study, approved by the U of M’s Stem Cell Research Oversight committee, brought the first embryo to a 27-day term. Because of the success of this phase, Daniel and Mary are currently seeking the committee’s approval to advance the research further into the later gestational period.

“We’re trying to take it in a phased approach,” Daniel said. “We want to be sure we address all of the possible issues — whether human cells go where we want them to go.”

“While it is a first phase, there’s pretty solid proof of concept,” Mary said. “We believe that we’ve proven that there’s no off-target effects of these cells, so we’re ready to move forward to later gestational stages.”

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