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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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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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Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche — ScienceDaily

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By transferring mouse aged hematopoietic stem cells (aged HSCs, *1) to the environment of young mice (bone marrow niche, *2), it was demonstrated that the pattern of stem cell gene expression was rejuvenated to that of young hematopoietic stem cells. On the other hand, the function of aged HSCs did not recover in the young bone marrow niche. The epigenome (DNA methylation, *3) of aged HSCs did not change significantly even in the young bone marrow niche, and DNA methylation profiles were found to be a better index than the gene expression pattern of aged HSCs.

A research group led by Professor Atsushi Iwama at the Division of Stem Cell and Molecular Medicine, The Institute of Medical Science, The University of Tokyo (IMSUT) announced these world-first results and was published in the Journal of Experimental Medicine (online) on November 24th.

“The results will contribute to the development of treatments for age-related blood diseases,” states lead scientist, Professor Iwama at IMSUT.

Focus on changes in aged HSCs in the bone marrow niche

The research group investigated whether rejuvenating aged HSCs in a young bone marrow niche environment would rejuvenate.

Tens of thousands of aged hematopoietic stem/progenitor cells collected from 20-month-old mice were transplanted into 8-week-old young mice without pretreatment such as irradiation. After two months of follow-up, they collected bone marrow cells and performed flow cytometric analysis.

The research team also transplanted 10-week-old young mouse HSCs for comparison. In addition, engrafted aged HSCs were fractionated and RNA sequence analysis and DNA methylation analysis were performed.

They found that engrafted aged HSCs were less capable of producing hematopoietic cells than younger HSCs. They also showed that differentiation of aged HSCs into multipotent progenitor cells was persistently impaired even in the young bone marrow niche, and that the direction of differentiation was biased. It was found that the transfer of aged HSCs to the young bone marrow niche does not improve their stem cell function.

A more detailed analysis may reveal mechanisms that irreversibly affect aged HSC function

Aging studies focusing on HSCs have been actively pursued in mice using a bone marrow transfer model. However, the effect of aging on HSCs remains to be clarified.

Professor Iwama states as follows.”This study has a significant impact because it clarified the effect of aging on HSCs. Our results are expected to contribute to further elucidation of the mechanism of aging in HSCs and understanding of the pathogenic mechanism of age-related blood diseases.”

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New insights into the mechanisms of neuroplasticity — ScienceDaily

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Reactive oxygen molecules, also known as “free radicals,” are generally considered harmful. However as it now turns out, they control cellular processes, which are important for the brain’s ability to adapt — at least in mice. Researchers from the German Center for Neurodegenerative Diseases (DZNE) and the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden published the findings in the journal Cell Stem Cell.

The researchers focused on the “hippocampus,” a brain area that is regarded as the control center for learning and memory. New nerve cells are created lifelong, even in adulthood. “This so-called adult neurogenesis helps the brain to adapt and change throughout life. It happens not only in mice, but also in humans,” explains Prof. Gerd Kempermann, speaker of the DZNE’s Dresden site and research group leader at the CRTD.

A trigger for neurogenesis

New nerve cells emerge from stem cells. “These precursor cells are an important basis for neuroplasticity, which is how we call the brain’s ability to adapt,” says the Dresden scientist. Together with colleagues he has now gained new insights into the processes underlying the formation of new nerve cells. The team was able to show in mice that neural stem cells, in comparison to adult nerve cells, contain a high degree of free radicals. “This is especially true when the stem cells are in a dormant state, which means that they do not divide and do not develop into nerve cells,” says Prof. Kempermann. Current study shows that an increase in the concentration of the radicals makes the stem cells ready to divide. “The oxygen molecules act like a switch that sets neurogenesis in motion.”

Free radicals are waste products of normal metabolism. Cellular mechanisms are usually in place to make sure they do not pile up. This is because the reactive oxygen molecules cause oxidative stress. “Too much of oxidative stress is known to be unfavorable. It can cause nerve damage and trigger aging processes,” explains Prof. Kempermann. “But obviously this is only one aspect and there is also a good side to free radicals. There are indications of this in other contexts. However, what is new and surprising is the fact that the stem cells in our brains not only tolerate such extremely high levels of radicals, but also use them for their function.”

Healthy aging

Radical scavengers, also known as “antioxidants,” counteract oxidative stress. Such substances are therefore considered important components of a healthy diet. They can be found in fruits and vegetables. “The positive effect of antioxidants has been proven and is not questioned by our study. We should also be careful with drawing conclusions for humans based on purely laboratory studies,” emphasizes Kempermann. “And yet our results at least suggest that free radicals are not fundamentally bad for the brain. In fact, they are most likely important for the brain to remain adaptable throughout life and to age in a healthy way.”

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New insights into Fragile X syndrome and the fetal brain — ScienceDaily

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Researchers at Tohoku University have revealed further insight into the fetal development of our brain and the potential causes of Fragile X syndrome (FSX).

During brain development, the fetal period is vital in creating neurons from neural stem cells to build up a functional adult brain. Any impairment in the developmental program could result in severe defects in the brain.

FSX is a genetic disorder characterized by intellectual disability and autistic symptoms. Children with FSX will generally suffer from developmental delays as well as social and behavioral problems.

FSX patients have a defect in the fragile X mental retardation 1 (FMR1) gene, a gene that codes for the fragile X mental retardation protein (FNRP) — the critical factor in normal brain development.

“Our study illustrated the possible molecular mechanism that causes FXS in the fetal brain and furthers our understanding of hereditary developmental disorders in the brain’s developmental stage,” said Noriko Osumi, professor at the Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine.

Using next-generation sequencing, Osumi and her team identified hundreds of FMRP regulated molecules in mice fetal brains. These molecules were associated not only with neurogenesis but also autism and intellectual disability.

Their findings showed that specific groups of molecules were involved in the intracellular signaling pathways such as Ras/MAPK, Wnt/?-catenin, and mTOR.

The mTOR activity was significant in the fetal brain of FMR1 deficient mice, suggesting that increased mTOR activity may lead to abnormal proliferation and differentiation of neural stem cells in the fetal brain. Ultimately, these molecular mechanisms could be responsible for developing the brain during the fetal period and contribute to the causes of FXS.

The research team hopes this new information will serve as an essential resource for future studies of neurodevelopmental disorders.

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Growing human organs for transplantation with new proof-of-concept — ScienceDaily

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In a new paper published in Stem Cell Reports, Bhanu Telugu and co-inventor Chi-Hun Park of the University of Maryland (UMD) Department of Animal and Avian Sciences show for the first time that newly established stem cells from pigs, when injected into embryos, contributed to the development of only the organ of interest (the embryonic gut and liver), laying the groundwork for stem cell therapeutics and organ transplantation. Telugu’s start-up company, Renovate Biosciences Inc. (RBI), was founded with the goal of leveraging the potential of stem cells to treat terminal diseases that would otherwise require organ transplants, either by avoiding the need for transplants altogether or creating a new pipeline for growing transplantable human organs. With the number of people who suffer from organ failures and the 20 deaths per day in the U.S. alone purely from a lack of available organs for transplant, finding a new way to provide organs and therapeutic options to transplant patients is a critical need. In this paper, Telugu and his team are sharing their first steps towards growing fully transplantable human organs in a pig host.

“This paper is really about using the stem cells from pigs for the first time and showing that they actually can be injected into embryos and only go to the endodermal target organs like the liver, which is very important for delivering safe therapeutic solutions going forward,” says Telugu. “This is an important milestone. It’s a pipe dream in a way because a lot of things need to work out between here and full organ transplantation, but this paper sets the stage for all our future research. We can’t really just go and start working with humans in work like this, so we started with pig-to-pig transfer in this paper, working with the stem cells and putting them back into other pigs to track the process to make sure it is safe for liver production as proof-of-concept.”

Telugu and his team pitched this work at UMD Bioscience Day on behalf of his company, RBI, and received the Inventor Pitch Award and the UMD Invention of the Year Award in 2018. In order to protect the intellectual property, Telugu worked with the UMD Office of Technology Commercialization (OTC) to secure patents and open the work up for additional fundraising to carry this technology through the preclinical and clinical stages. The Maryland Stem Cell Foundation provided some funding to advance this work, and Telugu is thankful that Maryland funds technologies in the human stem cell space.

“There are many terminal cases where people need some sort of an organ replacement, like organ failure and degenerative diseases that cannot be cured by drugs,” explains Telugu. “The traditional paradigm is to find a donor organ, but as of today there are still thousands of patients waiting for transplants, and there is no keeping up with the demand. Researchers have thought for a long time that stem cells could help solve this problem, and these stem cells have the ability to go into a specific organ as opposed to those that go into any lineage. In this case, you can differentiate the cells and place them where they are needed to help rescue a diseased organ, eliminating the need for transplant or at least buying the patient some time. Just making the human liver and collecting them early from a neonatal piglet, the hepatocyte [liver] cells alone are a $3 billion opportunity per year. And in the future, we can move into organ transplantation, first with the liver, and then looking at other organs of interest like the pancreas and lungs.”

According to Telugu, this has distinct advantages over other methods that researchers are currently using to create donor organs in pigs, since the organs Telugu and his team are working with are actually of human origin and are therefore more likely to be accepted when transplanted. “Transplant rejections are pretty common even between humans and humans,” says Telugu, “and if it is such a problem normally, you can imagine how an organ from a pig could be difficult to accept and may not essentially perform the same functions. Pig proteins may not function the same, so that remains a huge barrier for other methods that are not actually growing fully human organs like ours.”

This work has the potential to solve a major problem in the treatment of organ failure and other degenerative diseases, which is what Telugu and his work is all about. “Being a veterinarian by training, we always look at the problem and try to find solutions to them,” says Telugu. “Most animal scientists operate by looking for solutions, so integrating research and entrepreneurship to get this to the market where it is needed is essential. We are one of the few groups on the planet that are working in this space, and we have a great team of embryologists here at Maryland to do this work. We are uniquely positioned to accomplish this with both genome editing and stem cell biology expertise, and being able to prove the concept with this paper is a great first step towards our goals.”

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Materials provided by University of Maryland. Original written by Samantha Watters. Note: Content may be edited for style and length.

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Surprisingly simple method could provide a new tool for producing specialized cytoplasm for reproductive medicine — ScienceDaily

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In a new study published in the journal Nature, researchers in Japan report that activating just eight genes for producing gene-controlling proteins is enough to convert mouse stem cells directly into oocyte-like cells that mature and can even be fertilized like egg cells.

On top of providing new insights into the mechanisms of egg cell development, the research may lead to a simple route for generating highly specialized substances unique to oocytes for use in reproductive biology and medicine.

Stored in the body until they mature into egg cells ready for fertilization, oocytes represent the very first step in the creation a new human life.

Oocytes are extremely unique because of their ability to bring forth the over two hundred kinds of highly differentiated cells needed to create an individual person, and one key to this ability is the complex mixture of substances within the fluid-like cytoplasm filling the cells.

So extraordinary are oocytes and their cytoplasm that replacing an oocyte’s DNA-containing nucleus with that of a body cell — a process called somatic cell nuclear transfer — can produce a new life, as famously demonstrated with Dolly the sheep.

Thus, a fundamental understanding of oocytes and their development is important for both advancing reproductive medicine and better grasping how life propagates, but knowledge of the many genes that orchestrate oocyte development is still far from complete.

Analyzing the development of oocytes from mice, researchers led by Katsuhiko Hayashi, professor at Kyushu University’s Faculty of Medical Sciences, have now identified eight genes for gene-triggering proteins known as transcription factors that not only are necessary for oocyte growth but also can directly convert mouse stem cells into oocyte-like cells.

“I was initially in complete disbelief to see mouse stem cells so quickly and easily take the form of oocytes based on introducing just a handful of factors, but repeated experiments proved it was true,” says Nobuhiko Hamazaki, first author on the study reporting the results and assistant professor at Kyushu University at the time of the research. “To find that eight transcription factors could lead to such big changes was quite astonishing.”

Working in collaboration with researchers at RIKEN, Hayashi’s group found that both mouse embryonic stem cells and induced pluripotent stem (iPS) cells — which can be created from adult body cells — consistently converted into oocyte-like cells when forced to produce the set of eight transcription factors, with only four factors being sufficient in some cases though with worse reproducibility.

“That stem cells can be directly converted into oocyte-like cells without following the same sequence of steps that happen naturally is remarkable,” says Hayashi.

When grown in the presence of other cells usually found around oocytes, the oocyte-like cells developed structures similar to mature egg cells but with an abnormal chromosome structure. Despite this, the mature oocyte-like cells could be fertilized in vitro and exhibited early development, with some even progressing to an eight-cell stage.

Though the modified nuclei of the oocyte-like cells may not be useable in the long run, this is no problem for applications needing mainly the oocyte cytoplasm, such as for studies of reproductive biology and for treatments like mitochondrial replacement therapy, in which parts of oocytes are replaced to prevent mothers from passing to their children diseases related to the mitochondria.

“Cytoplasm from oocytes is an invaluable resource in reproductive biology and medicine, and this method could provide a novel tool for producing large amounts of it without any invasive procedures,” comments Hayashi. “While the processes could still be much more complex for humans, these initial results in mice are very promising.”

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