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January 2021

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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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Materials provided by American Academy of Neurology. Note: Content may be edited for style and length.

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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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Materials provided by Okayama University. Note: Content may be edited for style and length.

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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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SARS-CoV-2 infection demonstrated in a human lung bronchioalveolar tissue model — ScienceDaily

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Development of an in vitro human-derived tissue model for studying virus infection and disease progression in the alveolar cells of the lungs responsible for oxygen and carbon dioxide exchange with the blood might enable the study of possible therapies for acute respiratory distress syndrome (ARDS) triggered by SARS-CoV-2. Researchers in the Netherlands have demonstrated that the SARS-CoV-2 replicates efficiently in their model resembling the human bronchioalveolar system that is thought to play a critical role in progression of infection towards pneumonia and ARDS.

It is already established that in people infected with COVID-19 or some other respiratory viruses, alveolar injury can trigger a cascade of events that leads to ARDS, restricting transport of oxygen into the blood to dangerously low levels. There is also mounting evidence that the epithelium lining the alveoli plays a major role in progression of COVID-19. However, in vitro models for replicating disease progression in the alveoli of human lungs have proven difficult to establish, especially models that are also permissive to SARS-CoV-2 infection. This has greatly limited our understanding of COVID-19.

The Dutch team has now remedied this deficiency through application of self-renewing organoid models containing stem cells capable of differentiating into relevant cell types for study of disease processes. Organoids are tiny 3D tissues typically around 2 mm in diameter across derived from stem cells to mirror the complex structures of an organ, or at least to express selected aspects of it to meet a given biomedical research objective. Such organoids can then provide continuous sources of 2D tissues that mimic more accurately the geometry or cellular alignment of the structures under study.

A self-renewing organoid model for the epithelium of the airways conducting the gases, has already been developed by the same team, but the alveolar epithelium has proven a greater challenge to generate so far. The Dutch team has overcome this challenge and developed a 2D “air interface” system comprising a basal layer of stem cells in contact with the culture media and a top layer exposed to the air just as it would be in the lungs.

Multiple cultures were generated and infected successfully by SARS-CoV-2 targeting primarily alveolar type-II-like cells, known as ATII-L, confirmed by Transmission Electron Microscopy (TEM), surface marker stainings and single-cell sequencing. The study then shed light on the sequence of events following infection.

The study also identified through messenger RNA expression analysis a cellular immune response to the virus by infected cells. When the cultures were treated with the antiviral signaling molecule interferon lambda early in infection, SARS-CoV-2 replication was almost completely blocked, indicating that — when timed right — interferon lambda could be an effective treatment. These results also indicate that these cultures could be helpful for the development of a therapeutic intervention against acute respiratory distress syndrome (ARDS) from COVID-19.

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Materials provided by EMBO. Note: Content may be edited for style and length.

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