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Looking Ahead as the Discovery of Insulin Turns 100

<p><em>100 years ago, researchers purified insulin and transformed the lives of people with diabetes. Breakthroughs in stem cell research are providing potential opportunities to transform the next 100 years of treatment.</em></p>
<p>While technology has certainly improved, people with <a href="https://www.closerlookatstemcells.org/stem-cells-medicine/diabetes/">type 1 diabetes</a> (T1D) conceptually treat their disease in much the same way as <a href="https://collection.sciencemuseumgroup.org.uk/people/cp167047/leonard-thompson">patients were treated a century ago</a>. People with T1D lack insulin, a hormone required to process sugar into energy. To survive, patients must replace this insulin. For the last 100 years, diabetics have injected themselves multiple times a day with insulin using a syringe or a pump, but today, scientists are attempting to revolutionize this treatment using stem cells.&nbsp; &nbsp;</p>
<p>T1D is an autoimmune disease where the body kills the cells in the pancreas that normally make insulin to control blood sugar levels, known as &beta; (beta) cells. Unfortunately, the pancreas cannot regenerate &beta; cells, and consequently people with T1D must rely on supplemental insulin for their entire lives. This process is not as precise as having functional &beta; cells and reliance on lifelong insulin has tremendous health and economic burdens.</p>
<p>Scientists are working to use stem cells to replace &beta; cells and provide a new type of treatment. <a href="https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/">Pluripotent stem cells</a> are a versatile type of stem cell that can be coaxed into most cell types found in our bodies, including pancreatic &beta; cells. Researchers have succeeded in turning stem cells into &beta; cells, which can now be transplanted into patients to produce the necessary insulin. If this treatment is successful, it could potentially cure people of T1D, and the patients would no longer need to inject themselves with insulin (learn more in this short <a href="https://www.youtube.com/watch?v=9CFD7u4mHng">video</a> from the Harvard Stem Cell Institute, USA).</p>
<p>The process of turning stem cells into &beta; cells in the laboratory is sophisticated. Scientists working in the lab first had to determine how to replicate the way the pancreas develops in the human body. Given the limited knowledge of human fetal development, stem cell biologists conducted many studies to determine the specific genes that regulate &beta; cell development in humans. During the last 15 years, several research groups have independently used this information to successfully make &beta; cells from stem cells, creating a path forward for stem cell-based T1D treatments.</p>
<p>Strikingly, researchers found that &beta; cells derived from stem cells in the lab can perform the key functions of their counterparts found in the human body, including making insulin in response to sugar. When transplanted into diabetic mice, stem cell-derived &beta; cells can regulate sugar metabolism and improve the mouse&rsquo;s diabetic condition. Importantly, the mice survive without supplemental insulin &ndash; an important preclinical result that set the stage for clinical trials.&nbsp; &nbsp; &nbsp;&nbsp;</p>
<p>Last year, the U.S. Food Drug Administration (FDA) approved the first clinical trial of a pluripotent stem cell-based therapy for treating T1D. Initiated by ISSCR past-president Douglas Melton, PhD, Harvard University, USA and Vertex Pharmaceuticals, this trial tests whether transplanting stem cell-derived &beta; cells in people with T1D is effective and safe.</p>
<p>In October 2021, the scientific team carrying out this clinical trial <a href="https://www.nytimes.com/2021/11/27/health/diabetes-cure-stem-cells.html">reported</a> initial positive <a href="https://hsci.harvard.edu/news/new-therapy-treating-type-1-diabetes">results</a> from their first patient, Brian Shelton. After relying on supplemental insulin for about 40 years, Brian was able to produce his own insulin 90 days after receiving a single infusion of stem cell-derived insulin-producing &beta; cells, nearly eliminating his dependency on insulin injections.</p>
<p>In an alternative approach to transplanting mature &beta; cells, another biotechnology company, ViaCyte, is transplanting what are called stem cell-derived precursor cells, which mature and become functional once in the human body. The unique aspect of this strategy is that the immature cells have the ability to develop into &beta; cells as well as other cell types that regulate sugar metabolism.</p>
<p>ViaCyte released preliminary <a href="https://www.wtvr.com/news/local-news/promising-new-study-could-be-life-changing-for-type-1-diabetics">results from its clinical trial</a> in December 2021. The company reported on 15 patients and saw that the transplanted stem cell-derived precursor cells did indeed mature into cells that regulated sugar metabolism in people with T1D.</p>
<p>Together, these initial clinical trial results demonstrate the potential to use stem cell-derived cell products to treat people with T1D.</p>
<p>Before these therapies receive approval outside of clinical trials, further studies are necessary. It is important to test these treatments in more patients, examine possible long-term effects, and better protect the transplanted cells from attack by the patient&rsquo;s immune system.&nbsp;</p>
<p>These achievements in stem cell research are important milestones that move us closer to a cure for T1 diabetes and that have the potential to benefit the estimated 9 million people worldwide like Brian who are living with the chronic disease.</p>
<p>—<br />
<br />
Blog by guest contributor S.C. Jacky Sun, PhD candidate in the labs of Ed Stanley and Andrew Elefanty at the&nbsp;<a href="https://www.mcri.edu.au/">Murdoch Children&rsquo;s Research Institute</a>, Melbourne.</p>

Modeling the Body on a Few USB Sticks: The Power of Organs-on-Chips

<p>Shallow breath in, shallow breath out. Your diaphragm contracts as you inhale, creating a vacuum, drawing air into your lungs. Then it relaxes as you exhale, pushing the air out. Whether you experienced this after a run last week, or the memory is ingrained from gym class, one thing is for sure: your lungs require mechanical forces to develop and function throughout life. It is critical to model the complex and dynamic forces that our organs depend on, both to understand how they develop and what goes wrong when they fail.</p>
<p>While many biomedical advances have been made studying cells in isolation, researchers are learning that the closer they can approximate experimental conditions to the complexities of the human body, the better chance they have of identifying new treatments.</p>
<p>Just over 10 years ago, scientists developed a new way to study human organs in the lab, called organs-on-chips (OoCs) (see Figure 1). These small devices, the size of USB sticks, are made up of two major components: a clear, flexible, porous membrane and living human cells, which are often derived from stem cells. The flexible membrane has hollow channels that allow air and fluids, such as blood, to flow through the cells &mdash;something other models simply can&rsquo;t do. As a result of this ability, OoCs can be used to model complex organ structure and function, from brain to belly. The flow of fluids in these channels makes OoCs a much better representation of the human body that traditional models of static cells in Petri dishes.</p>
<p><strong><em><img src="https://www.closerlookatstemcells.org/wp-content/uploads/2021/12/ooca.tmb-medium.jpg" data-displaymode="Thumbnail" alt="OoCa" title="OoCa" style="float: left; margin-right: 5px;" />Figure 1. </em></strong><em>An example of an organ-on-chip. Chambers of cells sit in the middle of the rectangular device. Tubes allow for the flow of fluids, which could include immune cells, bacteria, or drugs. Credit: <a href="https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(21)00431-8">Mummery and Loskill, 2021, Stem Cell Reports</a>.</em></p>
<p>As an example, scientists can derive cardiomyocytes &mdash; muscle cells responsible for making a heart beat &mdash; from human <a href="https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/#induced-pluripotent">induced pluripotent stem cells</a> and use OoCs to mimic the environment cardiomyocytes would normally experience in the body. Mimicking natural conditions by integrating mechanical stress, electrical sensors, and fluid flow improves heart cell maturation, and remarkably these muscle cells will &ldquo;sync up&rdquo; and beat together. This heart-on-a-chip model has potential applications for drug screening, drug delivery, and toxicology studies.</p>
<p>Additionally, OoCs can be personalized, using cells from a specific patient to test whether they might respond to a treatment, a technology that is being called patient-on-chip or more informally, you-on-chip. Cells from the patient can be reprogrammed into stem cells in the lab, which are then coaxed into the cell type needed for testing and then applied to the patient-on-chip. Scientists can then apply various treatments to the patient-derived cells to see which might be effective, before treating the patient. Scientists can test thousands of drugs on patients-on-chips to potentially uncover personalized medicines.</p>
<p>But the ability of OoCs doesn&rsquo;t stop there. These chips can be combined to create what&rsquo;s been termed a body-on-chip or physiome-on-chip. In one instance, scientists managed to build 10 different organs in a chip, which they maintained for four weeks. These advanced models have the potential to more closely mimic the human body (see Figure 2).</p>
<p><strong><em><img src="https://www.closerlookatstemcells.org/wp-content/uploads/2021/12/loskiletal.tmb-medium.jpg" data-displaymode="Thumbnail" alt="loskiletal" title="loskiletal" style="float: left; margin-right: 5px;" />Figure 2. </em></strong><em>Researchers are building more complex models to more closely approximate the human body. Using organ-on-chips from multiple organs allows scientists to model full organ systems and look for potential novel treatments. Credit: Adapted from <a href="https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(21)00422-7">Loskill et al, 2021, Stem Cell Reports</a>.</em></p>
<p>Researchers have used the physiome-on-chip to make interesting discoveries regarding the interaction between organs. Scientists used this model to study how gut and liver interactions impact ulcerative colitis&mdash;an inflammatory bowel disease causing inflammation and ulcers or sores in the large intestine. Strikingly they found that when they connected a gut-on-chip comprised of cells from a patient with ulcerative colitis to a healthy liver-on-chip, inflammation in the diseased gut was reduced! Further studies could identify the factors that led to this reduced inflammation.</p>
<p>In this new experimental model engineers and biologists are collaborating to understand biology and disease, with potential applications to benefit human health. Whether it&rsquo;s personalized medicine for patients or studying the effects of pharmaceuticals on several organs simultaneously in a miniaturized system, OoCs have already begun to help shape how we approach model systems and health as a whole.<br />
<p>Blog by guest contributor, Parmin Sedigh. If you would like to learn more about organs-on-chips, their applications, and future prospects, read the OoC <em>Stem Cell Reports</em> special issue <a href="https://www.cell.com/stem-cell-reports/issue?pii=S2213-6711(20)X0010-5">here</a> and listen to &ldquo;The Intersection of Stem Cells and Engineering&rdquo; on&nbsp; The Stem Cell Report with Martin Pera <a href="https://thestemcellreport.buzzsprout.com/">here</a>.</p>

Skyrocketing Science with Stem Cells in Space

<p>Do you think stem cells floating in space could possibly help us down on Earth? This might sound far out, but scientists are finding that researching stem cells outside our planet could help us better understand the physiological changes to astronauts in orbit and, more broadly, provide key insights about disease progression and treatment on Earth.</p>
<p><strong>When stem cells are out of this world</strong></p>
<p>Space travel plucks us away from the pull of Earth&rsquo;s gravity and exposes us to solar radiation &ndash; novel conditions that provide new opportunities for research. While it is impractical to send a whole team of biologists to space, extraterrestrial physiology can still be studied by preparing cells on Earth, sending them to the International Space Station (ISS) and monitoring them remotely using automated experimental systems such as Space Tango&rsquo;s CubeLab and NASA&rsquo;s Bioculture System.</p>
<p>With these technologies, scientists sent <a href="https://www.stembook.org/node/32247">human stem cell-derived heart cells to space</a> for the first time in 2016 (see Figure 1). Dr. Joseph Wu, Stanford University, USA, found that these beating cells behaved differently in microgravity, yet returned to normal once back on earth. This study revealed the remarkable adaptability of human heart cells to changing environmental conditions, setting the stage for future experiments.</p>
<p>To take innovative stem cell research like Dr. Wu&rsquo;s to the next level, NASA is constructing the Integrated Space Stem Cell Orbital Research (ISSCOR), a dedicated <a href="https://www.washingtonpost.com/science/stem-cells-in-space/2020/12/04/8915f700-2471-11eb-a688-5298ad5d580a_story.html">state-of-the-art stem cell lab within the ISS</a> whose mission is to apply the power of stem cells in space to improve quality of life on Earth.</p>
<img src="https://www.closerlookatstemcells.org/wp-content/uploads/2021/11/kate_rubins-heart_cells.tmb-300×400-1.jpg" data-displaymode="Thumbnail" alt="Kate_Rubins-heart_cells" title="Kate_Rubins-heart_cells" style="vertical-align: middle;" />
<p><strong><br />
Figure 1. </strong>NASA Astronaut Kate Rubins works to set up a new microscope onboard the space station for the Effects of Microgravity on Stem Cell-Derived Heart Cells investigation. MEDIA CREDIT:&nbsp;Image courtesy of NASA TV.</p>
<p><strong>Cancer research with cosmic radiation</strong></p>
<p>Dr. Catriona Jamieson, University of California, San Diego, USA, is one of the scientists utilizing ISSCOR to improve treatments for patients on earth. Solar radiation breaks and mutates our DNA, leading to cancer. <a href="https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/#tissue-specific">Tissue stem cells</a>, long-lived cells that replenish specific tissues, are particularly vulnerable to this accumulation of DNA damage. For instance, blood stem cells exposed to cosmic levels of radiation transition more rapidly to a precancerous state, allowing scientists to study disease progression at an accelerated pace compared to that on Earth. In addition, being in space causes the immune cells in contact with cancer cells to malfunction. By studying early onset blood cancers and immune reactivation syndromes in space, Dr. Jamieson is hoping to rapidly identify treatments that can be translated to clinical trials.</p>
<p><strong>Experimenting with zero gravity</strong></p>
<p>Microgravity has long been known to have detrimental effects on astronauts&rsquo; bodies, and recent research is finding stem cells may be the culprits. For example, astronauts who spend extended time in space often contract a condition known as space anemia, which is caused in part by the decreased production of red blood cells, our body&rsquo;s transporters of oxygen and nutrients, which come from blood stem cells.</p>
<p>The absence of gravitational force can change the physiology of many other cell types, and Dr. Valentina Fossati, <a href="https://nyscf.org/">New York Stem Cell Foundation</a>, USA, is taking advantage of this to try to find treatments for diseases such as Parkinson&rsquo;s disease and multiple sclerosis. Microgravity can influence immune cell function and their interactions with neurons, while also mimicking aging in stem cells, allowing for novel investigations. Dr. Fossati is therefore launching stem cell-derived <a href="https://www.eurostemcell.org/ethics-brain-organoids">brain organoids</a>, 3D models of the brain, into space in the hopes of unlocking the secrets to <a href="https://nyscf.org/resources/nyscf-scientists-talk-space-stem-cells-and-their-pioneering-study-of-ms-and-pd/">fighting age-related neurodegenerative disorders</a>.</p>
<p><strong>Regenerative medicine of the future?</strong></p>
<p>Scientists hope to one day be able to use stem cells as a reliable source of healthy functional cells that can be transplanted into patients to treat a variety of conditions. For such transplantation therapy to be successful, billions and billions of cells may be required, which can be difficult to achieve in the laboratory. Unprecedently, multiple studies have shown that various stem cells actually grow better in space than in their usual earthly conditions. Stem cells grown in space may also be better at integrating into the appropriate tissue upon transplantation, as microgravity triggers favorable changes in cellular architecture. By studying the mechanisms behind these phenomena, researchers may find ways to promote stem cell expansion and tissue integration to improve stem cell therapy.</p>
<p>Stem cells in space are being studied in pursuit of developing therapeutics for diseases from cancer and aging to neurodegenerative and heart diseases. Thus, learning more about stem cells in space is not only significant for understanding the impact of extraterrestrial travel on the body but can also make significant contributions to terrestrial human health. </p>
<p>Blog by guest contributor Kevin Gonzales, PhD, postdoctoral fellow in the lab of Elaine Fuchs at The Rockefeller University, NY, USA. To learn more register for our Digital Series &ldquo;<a href="https://www.isscr.org/meetings-events/isscr-digital/stem-cells-in-space">Stem Cells in Space</a>.&rdquo;</p>

Setting the Standards – New Stem Cell Research Guidelines Released

<center><img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-23-n1k71z-scaled.jpg” />
<span class=”attribution”><span class=”source”>Paul Sakuma/AP</span></span>
<span><a href=”https://theconversation.com/profiles/megan-munsie-756″>Megan Munsie</a>, <em><a href=”https://theconversation.com/institutions/the-university-of-melbourne-722″>The University of Melbourne</a></em> and <a href=”https://theconversation.com/profiles/melissa-little-333629″>Melissa Little</a>, <em><a href=”https://theconversation.com/institutions/murdoch-childrens-research-institute-1027″>Murdoch Children’s Research Institute</a></em></span>
<p>The International Society for Stem Cell Research (ISSCR) today <a href=”https://www.isscr.org/policy/guidelines-for-stem-cell-research-and-clinical-translation”>released updated guidelines</a> for stem cell research and its translation to medicine. </p>
<p>Developed in response to recent scientific and clinical advances, the revised guidelines provide a series of detailed and practical recommendations that set out global standards for how these emerging technologies should be harnessed.</p>
<p>Stem cell research has <a href=”https://www.closerlookatstemcells.org/from-lab-to-you/stem-cells-and-research/”>huge potential</a> &mdash; it could help pave the way for new therapies for ailments ranging from Parkinson&rsquo;s disease to childhood kidney failure. But scientific advances in this field can present unique ethical and policy issues beyond that seen in other areas of medical research.</p>
<p>The science is advancing at breakneck pace. Just in the past couple of months, we have seen <a href=”https://theconversation.com/researchers-have-grown-human-embryos-from-skin-cells-what-does-that-mean-and-is-it-ethical-157228″>model human embryos grown from skin cells</a>, and the creation of <a href=”https://theconversation.com/as-scientists-move-closer-to-making-part-human-part-animal-organisms-what-are-the-concerns-159049″>human-monkey embryos</a> for use in research. </p>
<p>The ISSCR has long recognised the need to set clear ethical boundaries for stem cell research. Previous guidelines have provided advice on techniques such as the use of human embryos to create stem cells, and set the required standards when using these technologies to create new medicines. </p>
<p>They have also explicitly banned certain practices, such as <a href=”https://theconversation.com/dolly-the-sheep-and-the-human-cloning-debate-twenty-years-later-63712″>reproductive cloning</a> and the <a href=”https://theconversation.com/private-clinics-peddling-of-unproven-stem-cell-treatments-is-unsafe-and-unethical-80608″>sale of unproven therapies that claim to be made of stem cells</a>. </p>
<p>The 2021 guidelines &mdash; an update on the previous version, released in 2016 &mdash; aim to set standards for the many recent advances in stem cell and human embryo research. These include &ldquo;chimeric&rdquo; embryos containing cells from humans and other animals, &ldquo;organoids&rdquo; grown from stem cells to create tissue that resembles particular human organs, and &ldquo;models&rdquo; of human embryos &mdash; arrangements of human cells that mimic the early stages of embryo development. </p>
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<center><a href=”https://theconversation.com/growing-human-embryos-in-the-lab-and-why-scientists-just-tweaked-the-rules-podcast-161611″><img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-15-1crjmoe.png” alt=”Promotional image for podcast” width=”100%” /></a></center>
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<h2>So what&rsquo;s new?</h2>
<p>The guidelines contain a clear requirement for certain new stem cell research approaches only to be conducted after a specialised review process. This review should be independent of the researchers, and include community members as well as people with expertise in the relevant science, ethics and law. </p>
<p>This is beyond what is typically required by a university or research institute where medical research is conducted. Besides evaluating the merit of the proposed research, the new reviews should also consider whether there are alternative ways to do the research, the source of stem cells and how they were obtained, and the minimum time required to reach the research goals, particularly in relation to human embryo and related research.</p>
<figure class=”align-center “>
<img alt=”Human embryos” src=”https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-13-gn1h3j-6.jpg” srcset=”https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-13-gn1h3j.jpg 600w, https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-13-gn1h3j-1.jpg 1200w, https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-13-gn1h3j-2.jpg 1800w, https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-13-gn1h3j-3.jpg 754w, https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-13-gn1h3j-4.jpg 1508w, https://www.closerlookatstemcells.org/wp-content/uploads/2021/08/file-20210527-13-gn1h3j-5.jpg 2262w” sizes=”(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px” />
<span class=”caption”>The new guidelines call for a debate on whether to extend the current 14-day limit for experimentation on human embryos.</span>
<span class=”attribution”><span class=”source”>Oregon Health Sciences/AP</span></span>
<p>Specialised review is not a new concept. The previous guidelines required it when researchers made stem cells from human embryos or sought to culture human embryos in the lab. But now researchers will now also be required to seek higher review when they create model embryos such as <a href=”https://theconversation.com/researchers-have-grown-human-embryos-from-skin-cells-what-does-that-mean-and-is-it-ethical-157228″>blastoids</a>, or study the development of animal-human embryos in animal wombs. </p>
<p>Researchers developing <a href=”https://theconversation.com/3-parent-ivf-could-prevent-illness-in-many-children-but-its-really-more-like-2-002-parent-ivf-126591″>new therapies for mitochondrial disease</a> will also be required to seek higher-level review before attempting to transfer to the uterus of a woman human embryos in which affected mitochondria (a part of the cell&rsquo;s energy-production apparatus) have been replaced.</p>
<p>Importantly, the revised guidelines also clearly rule out certain activities. These continue to include reproductive cloning and attempts to form a pregnancy in a woman from <a href=”https://theconversation.com/chinas-failed-gene-edited-baby-experiment-proves-were-not-ready-for-human-embryo-modification-128454″>genetically &ldquo;edited&rdquo; human embryos</a> or from model embryos made from stem cells. Prohibited activities also now include using eggs and sperm made from human stem cells for reproduction, or transferring a human-animal chimeric embryo into the uterus of a woman or an ape.</p>
<hr />
Read more:
<a href=”https://theconversation.com/chinas-failed-gene-edited-baby-experiment-proves-were-not-ready-for-human-embryo-modification-128454″>China’s failed gene-edited baby experiment proves we’re not ready for human embryo modification</a>
<hr />
<p>The guidelines also call for a public conversation about whether we should allow limited lab research on human embryos beyond the <a href=”https://www.nature.com/articles/d41586-018-05586-z”>existing limit of 14 days&rsquo; development</a>. Historically, it has not been possible to support human embryonic development outside the body beyond this stage. However, recent advances in human embryo culture raise the possibility that this may now be technically feasible. </p>
<p>Extending the amount of time in culture – in terms of days – could potentially yield new treatments for developmental conditions or infertility, but will also raise concerns about whether possible benefits justify this research. Any decisions to overturn this long-held signpost would need to be carefully deliberated and take into consideration existing law, community values and discussion around what the new limit should be. </p>
<p>The revised guidelines also reinforce the need for informed consent for the collection of human material and participation in stem cell clinical trials, and reiterate that no new stem cell treatment should be made available before it is tested for safety and effectiveness in well-designed and publicly visible clinical trials. The ISSCR continues to condemn the commercial use of unproven stem cell treatments.</p>
<h2>Why do these guidelines matter?</h2>
<p>While stem cell science holds much promise, it is paramount that research is scientifically and ethically rigorous, with appropriate oversight, transparency and public accountability.</p>
<p>The fact these guidelines are driven by experts &ndash; including stem cell scientists, doctors, ethicists, lawyers and industry representatives &ndash; from across 14 countries indicates a deep sense of responsibility and integrity within the research community, and a desire to ensure science remains in step with community values.</p>
<p>However, these guidelines are recommendations, not laws. </p>
<p>Researchers will need to abide by their respective national or state regulations and ethical standards. Some countries already have regulatory frameworks that are consistent with the new recommendations. In other places there is no national guidance around laboratory and clinical stem cell research at all, or existing law touches on some but not all of the emerging applications of stem cell research. </p>
<hr />
Read more:
<a href=”https://theconversation.com/as-scientists-move-closer-to-making-part-human-part-animal-organisms-what-are-the-concerns-159049″>As scientists move closer to making part human, part animal organisms, what are the concerns?</a>
<hr />
<p>For example, in Australia there is already an established pathway for higher-level review of embryo models created from stem cells. However, the same legislation currently bans any attempt to use mitochondrial transfer techniques to create embryos for research or to achieve a pregnancy &ndash; both of which are permissible under the new ISSCR guidelines. </p>
<p>Rather than attempting to impose a set of hard-and-fast rules on an ever-evolving research field, the new guidelines attempt to address emerging issues and drive important discussions at domestic level. Ultimately, it is the public and the regulators who will need to set the standards.<!– Below is The Conversation’s page counter tag. Please DO NOT REMOVE. –><img src=”https://counter.theconversation.com/content/161578/count.gif?distributor=republish-lightbox-basic” alt=”The Conversation” width=”1″ height=”1″ style=”border: none !important; box-shadow: none !important; margin: 0 !important; max-height: 1px !important; max-width: 1px !important; min-height: 1px !important; min-width: 1px !important; opacity: 0 !important; outline: none !important; padding: 0 !important; text-shadow: none !important;” /><!– End of code. If you don’t see any code above, please get new code from the Advanced tab after you click the republish button. The page counter does not collect any personal data. More info: https://theconversation.com/republishing-guidelines –></p>
<p><span><a href=”https://theconversation.com/profiles/megan-munsie-756″>Megan Munsie</a>, Head Ethics, Education &amp; Policy in Stem Cell Science and Convener of Stem Cells Australia, <em><a href=”https://theconversation.com/institutions/the-university-of-melbourne-722″>The University of Melbourne</a></em> and <a href=”https://theconversation.com/profiles/melissa-little-333629″>Melissa Little</a>, Theme Director, Cell Biology, <em><a href=”https://theconversation.com/institutions/murdoch-childrens-research-institute-1027″>Murdoch Children’s Research Institute</a></em></span></p>
<p>This article is republished from <a href=”https://theconversation.com”>The Conversation</a> under a Creative Commons license. Read the <a href=”https://theconversation.com/new-global-guidelines-for-stem-cell-research-aim-to-drive-discussions-not-lay-down-the-law-161578″>original article</a>.</p>

I’ll Take My Burger with a Side of Sustainability

Imagine that a chef personally asks you to taste a new burger recipe. It looks medium rare as requested, has a satisfying texture, and most importantly, it tastes delightfully meaty. What if they tell you that the&nbsp;burger you just ate was better for animals, the environment, and your health? Then they tell you that the burger was not made from a cow, but rather, from stem cells in a lab. Does that change how you feel about your meal? </p>
<p>Every year, humans consume 77 billion land animals, which has far-reaching consequences on the environment. Animal agriculture has detrimental impacts on land use, greenhouse gas production, water pollution, and antibiotic resistance. The current rate of factory farming is not sustainable, but even with an awareness of the harm to our environment, the majority of meat consumers (including myself) are not yet ready to entirely abstain from meat. So, what else can we put on our plates? &nbsp;</p>
<p>From the perspective of the customer&rsquo;s palate, meat has three important attributes: taste, texture, and appearance. Thus, to recreate meat, we do not necessarily require a breathing animal, but rather a source of protein that looks like meat, tastes like meat, and has the same or better nutritional profile.. This is where stem cells enter the fray. It turns out that, over decades of research, scientists have discovered a lot about how muscle tissue, the main component of meat, develops in animals. Using this knowledge, researchers learned how to coax muscle stem cells, which can be isolated from a painless cow biopsy, to develop into muscle. By immersing the muscle stem cell in a liquid broth optimized for growth, it can expand one quadrillion times (that&rsquo;s 15 zeros) in less than two months. The expanded stem cells can be fostered to form muscle fibers, which in three weeks, are ready to be amassed into free-form meat, such as meatballs or burger patties (see Figure). In theory, just a single stem cell can make more than 50,000 burger patties (assuming a quarter pound each) in less than three months. Compare that with raising a cow for one and a half years for a maximum of 2,000 burgers.</p>

Figure: Cheeseburger derived from cultured meat. Credit: Mosa Meat, The Netherlands.

<p>These numbers are astounding, but they are not the only advantage of stem-cell based meat, or as it is more commonly called, &ldquo;clean meat&rdquo; or cultured meat. On top of obviating the environmental and ethical dilemma of relying on animal agriculture, cultured meat also provides an easy route for enhancing nutritional content by adding vitamins or other nutritional components during the culture process. Additional cell types added to the meat can replicate and enhance the taste and texture. Stem cells from accompanying tissues, such as fat, can be grown alongside muscle, and cells can be 3D-printed or grown in scaffolds to recreate the taste and texture of structured meats, such as fillets and steaks. Cultured meat therefore offers the potential for a more enjoyable, nutritious, ecological, and humane way to be a carnivore.</p>
<p>Obstacles, including that of public perception, however, remains. While anything new may come across as unnatural, untrustworthy, and ultimately unappetizing, this is mostly a psychological hurdle. If you think about it, we already consume cultured products like cheese and yogurt; the only difference is the starting cells used. Taste-tests by food critics and scientists have even determined that cultured meat is almost indistinguishable from its regular counterparts, and in <a href=”https://www.foodnavigator.com/Article/2020/04/20/Consumers-willing-to-pay-nearly-40-more-for-cultured-meat-over-regular-meat-study”>one study</a>, learning about its societal and personal benefits actually led to a higher taste rating and a willingness to pay more for the meat. Thus, given public education, proper framing, and time, cultured meat can become a competitive alternative to regular meat.</p>
<p>In recent years, the public&rsquo;s appetite has grown for another type of meat alternative – plant-based meats – which is already competing in the market &ndash; ever heard of Beyond or Impossible Burgers? Cultured meat is closely following this trajectory and has come a long way in terms of increasing production and lowering costs since the first proof-of-concept cultured burger back in 2013. In fact, the first cultured meat for commercial sale is now available in a restaurant called 1880 in Singapore – if you are curious to give it a taste.</p>
<p>Now doesn&rsquo;t your burger taste best with a side of sustainability?</p>
<p>Blog by guest contributor Kevin Gonzales, PhD, postdoctoral fellow in the lab of Elaine Fuchs at The Rockefeller University, NY, USA. To learn how else stem cells are being used in sustainability read &ldquo;<a href=”https://www.closerlookatstemcells.org/2021/03/02/can-stem-cell-research-save-endangered-species/”>Can Stem Cell Research Save Endangered Species</a>&rdquo; or register for our Digital Series &ldquo;<a href=”https://www.isscr.org/meetings-events/event-detail/2021/02/03/isscr-events/stem-cells-and-global-sustainability”>Stem Cells and Global Sustainability</a>.&rdquo;</p>

Can Stem Cell Research Save Endangered Species?

“It’s like witnessing a funeral,” a spectator whispers as the Tasmanian artist Lucienne Rickard chafes a rubber eraser against a pencil portrait of the swift parrot. This critically endangered bird migrates between southeastern mainland Australia and Tasmania, where it breeds. Rickard has been <a href=”https://www.tmag.tas.gov.au/whats_on/exhibitions/current_upcoming/info/extinction_studies”>drawing and then erasing</a> meticulous replicas of extinct and threatened species to alert viewers of the ongoing assault on Earth&rsquo;s biodiversity (Figure 1). Even the loss of a single species like the swift parrot can leave a large void in nature. Beyond the parrot&rsquo;s majestic beauty, migratory birds have been shown to promote biodiversity by transporting nutrients and other organisms, coupling otherwise disparate communities, and influencing the genetic mixing of the resident populations. If nothing is done, its foreseeable extinction will upset the balance in the forest ecosystem in which it dwells.</p>
<center><img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2021/03/caribbean-monk-seal-side-by-side.tmb-medium.jpg” data-displaymode=”Thumbnail” alt=”Caribbean Monk Seal side by side” title=”Caribbean Monk Seal side by side” /><br />
<p> <em>Figure 1: In the series &ldquo;Extinction Studies,&rdquo; Lucienne Rickard draws realistic, large-scale images of endangered and extinct species, and then erases them to represent their loss. Using the same piece of paper, the remnants and impressions of the previous species can be seen under the new sketch. Shown here is the Caribbean Monk Seal, now extinct after humans exploited them for their skins and oil and decimated their food source by overfishing. Credit: Lucienne Rickard, Extinction Studies project at Tasmanian Museum and Art Gallery, supported by Detached Cultural Organisation. For more information, please see the artist&rsquo;s Instagram account: @luciennerickard.</em></p></center>
<p>Many other species are facing eradication as the Earth undergoes its sixth mass extinction. In the past century alone, we have lost the same number of species that would typically have gone extinct over the course of about 10,000 years. Human behavior, including habitat degradation, pollution, factory farming, and animal exploitation, has led to calamitous changes to the natural world that have accelerated the extinction rate by 100 times or more, causing a rapid decline of biodiversity. Human innovation and changes to behavior, however, can slow down this annihilation of species through conscious environmental preservation, and surprisingly, stem cell research.</p>
<p>The role of stem cell research in species conservation is best exemplified by efforts to save the beloved rhino, whose populations have been driven to the brink of extinction by illegal poaching. Loss of the rhinoceros would jeopardize the grassland habitats of Africa and Asia where these megaherbivores play key roles in shaping the earth and vegetation upon which many other species depend. The most pressing case is that of the Northern White Rhino, which at present, has only two known living individuals left in the entire world, both infertile females (Figure 2). Because previous attempts at breeding this species in captivity were unsuccessful, researchers are currently using assisted reproductive technology and novel stem cell techniques to try to save this species.</p>
<p><center><img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2021/03/nola-2.tmb-medium.jpg” data-displaymode=”Thumbnail” alt=”Nola 2″ title=”Nola 2″ /></p>
<p> <em>Figure 2: Nola, the last Northern White Rhino in the United States, died in 2015 but her cells live on in the form of induced pluripotent stem cells made by researchers from the San Diego Zoo Institute for Conservation Research, USA in collaboration with the Scripps Research Institute, USA. Photo credit: San Diego Zoo Global.</em></p></center>
<p>Scientists previously collected sperm and eggs from several Northern White Rhinos. Through <em>in vitro fertilization</em> (IVF) scientists produced <a href=”https://www.avantea.it/fileadmin/user_upload/news/Press_Release_BioRescue_2021_01_14_inglese.pdf”>five Northern White Rhino embryos</a>, which have the potential to develop into mature animals. The researchers are hoping that the closely-related Southern White Rhino can function as a surrogate mother for these Northern White Rhino embryos and bear healthy Northern White Rhino calves.</p>
<p>The supply of eggs, however, is very limited and additional methods are needed. Scientists have therefore turned to stem cell research to try to create additional Northern White Rhino embryos, which could eventually help create a self-sustaining population.</p>
<p>In a landmark study in 2006, researchers determined that they could take a skin cell in the body and revert it to a stem cell state by <em>cellular reprogramming</em>. This creates what are known as <a href=”https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/#induced-pluripotent”>induced pluripotent stem cells</a> (iPSCs), which can give rise to all of the cells in an organism. The first Northern White Rhino iPSCs were reprogrammed in 2011, and today, there are iPSCs from 12 Northern White Rhinos, eight of which are not related. This is important for establishing genetic diversity and maintaining a healthy population. With this method, a single rhinoceros skin cell could be all we need to produce new rhinos.</p>
<p>In order for iPSCs to be used in conservation efforts, researchers must figure out how to directly convert iPSCs into embryos, or coax them to produce mature sperm and eggs for IVF. Both methods are currently being studied in mice. Once perfected using mouse iPSCs, the protocols will have to be adapted for the rhino. Until this time Northern White Rhino iPSCs can safely be maintained in the laboratory where they will be readily available once science advances. Successful creation of iPSCs from the Northern White Rhino jumpstarted efforts to preserve other endangered species using stem cells, including the Sumatran Rhino, estimated at fewer than 80 in existence.</p>
<p>Cellular reprogramming can be performed on virtually any cell from any species. This technology is therefore as applicable to extinct species as it is to endangered ones, as long as a viable cell is still available. The Frozen Zoo&reg; in San Diego, CA, USA, a <a href=”https://www.discovermagazine.com/planet-earth/saving-endangered-species-or-at-least-their-tissues-with-frozen-zoos”>frozen tissue bank</a>, has already preserved cells from more than 10,000 individuals representing 1,000+ species. With this in mind, scientists have begun research on reviving ecologically important extinct animals such as the passenger pigeon (a migratory bird like the swift parrot) and the wooly mammoth (a megaherbivore like the rhino).</p>
<p>The preservation and revival of species still relies, however, on the conservation of habitats in which they can thrive. We must act to protect the environment and the species that we still have, and hopefully humanity can thrive in a world where parrots still sail the skies and rhinos still roam the Earth.</p>
<p><em>To learn more, watch the four-part ISSCR Digital Series on species conservation, &ldquo;<a href=”https://www.isscr.org/meetings-events/isscr-digital/stem-cells-and-global-sustainability”>Stem Cells and Global Sustainability</a>,&rdquo; available on-demand now.</em></p>
<p>Blog by guest contributor Kevin Gonzales, PhD, postdoctoral fellow in the lab of Elaine Fuchs at The Rockefeller University, NY, USA.</p>

The Universe of Universal Stem Cells: Rewards vs Risks

Many incurable health problems are characterized by the death of cells that cannot regenerate or repair themselves upon damage or injury. For example, cardiac muscle cells die in heart attack, nerve cells perish in the brain during a stroke, and insulin-producing cells vanish in diabetes. Unfortunately, these cells are incapable of regeneration, leading to irreversible damage. Laboratory scientists are developing potential solutions to replace these cells. 

Stem cell scientists are studying the use of stem cells to produce functional cells that could be transplanted into patients to treat and potentially reverse the damage. Remarkably, scientists can take skin or blood cells and turn them into cells that can become any cell in the body, known as an induced pluripotent stem cells (iPSCs). These characteristics make iPSCs an accessible and versatile source for generating cells to replace those lost due to disease or damage. iPSCs can be made from anyone, and consequently could theoretically be used to make individual batches of replacement cells for every patient. However, such a process is inefficient and expensive. Scientists are working to make universal donor stem cells that could ideally be transplanted into anyone without immune rejection.

A key requirement for cell transplantation is an immune match between the donor and recipient to avoid immune rejection, just like organ transplants. The key factors governing this tissue compatibility are called the human leukocyte antigens (HLAs). They are expressed on the cell’s surface and enable the immune system to distinguish self from non-self, acting as a personal cell “ID card.” If HLAs between the donor cells are mismatched to the recipient, the immune system will identify the transplanted cells as foreign and attack and kill them. Such immune rejection can be life-threatening to the recipient. The probability of a perfect HLA match is about 1 in 100,000 between two unrelated individuals, representing a fundamental challenge for any transplantations, including cell-based therapies. 

A Universal Stem Cell Bank

To solve this problem, scientists have proposed several different strategies. In one proposed strategy, scientists are attempting to isolate and “bank,” or store, iPSCs that would be immunologically compatible with many different people. In another, researchers are using genetic approaches to engineer stem cells that would be accepted by any recipient.  

The Global Alliance for iPSC Therapies (GAiT) was established to create an international registry of clinical grade iPSCs. “This is similar to how the international bone marrow donor registry has worked, where the stem cells of a donor are available to recipients living in different countries,” says Associate Professor Ngaire Elwood, Director of the BMDI Cord Blood Bank in Melbourne, Australia, and a collaborator of Global Alliance for iPSC Therapies. Accordingly, banks like GAiT enable.” iPSC-based therapies by providing a resource to find compatible transplantable materials.

Researchers in some countries are undertaking efforts to establish iPSC lines that would be compatible with the majority of the population. In general, there is less genetic diversity in the Japanese population than in other countries and theoretically only a small number of iPSC lines would be needed to be HLA-compatible with a large proportion of the population. Nobel Laureate Shinya Yamanaka has led an effort at the Kyoto University Center for iPSC Research and Application to bank these compatible stem cell lines. So far, they have created 27 iPSC lines, which in principle, would be compatible with 40 percent of the Japanese population. Similarly, Cambridge University, UK scientists predict that as few as 150 selected donors would cover at least 90 percent of the UK population.

Genetic differences, however, may still cause immune rejection. In these cases, recipients would need to take immunosuppressant drugs long-term, which impairs their ability to fight off infections. An alternative transplant strategy is to create genetically modified stem cells that can completely hide from the immune system of anyone, so-called “universal” stem cells.

Creating Universal Stem Cells
Given that HLA mismatching is the chief barrier for cell transplantation, scientists have used gene-editing tools to inactivate key HLA genes of iPSCs. These bioengineered iPSCs, designated “universal” stem cells, are able to evade immune rejection and represent a unique approach to developing transplantable cells for genetically diverse populations. Inactivating the HLA genes in universal stem cells, however, does have a potential risk. HLA genes are required for the elimination of cancer cells and there is concern that should these universal cells become cancerous, that they could grow unchecked by the recipient’s immune system.

A potential solution to mitigate the risk is to include a mechanism that would kill the universal cells if needed. Andras Nagy’s team in Toronto, Canada is a leading the way in developing a “cell suicide system” to make universal stem cells safer. In this system, stem cells are engineered to contain a suicide switch that could be activated when the cells start showing any abnormalities, such as uncontrolled growth. As a result, problematic cells would be killed before they form tumors. 

“Universal cells require significant genetic manipulation, including a suicide switch, this approach will have a more difficult time being approved by the regulators for routine clinical use,” says Ngaire, who has 13 years of experience running a cell manufacturing facility licensed by the Therapeutic Goods Administrations in Australia.  

Either by banking iPS cells from a variety of donors or by genetically manipulating them, these approaches to using stem cells are laying the foundation to develop new transplantation treatments for incurable diseases. Like all currently available treatments, the balance of the benefits versus risks is the key consideration towards successful clinical translation. 

Blog by guest contributor S.C. Jacky Sun, PhD candidate in the labs of Ed Stanley and Andrew Elefanty at the Murdoch Children’s Research Institute, Melbourne.

Stem Cells May Offer Key to Treating Venomous Snake Bites

Each year people around the world fall victim to about 1.8 – 2.7 million venomous snake bites. Many of these injuries go untreated due to lack of access to available treatments or health insurance, resulting in more than 100,000 deaths and approximately three times as many permanent disabilities. New therapies are needed to treat snakebite envenoming, a neglected public health issue. A new therapeutic tool to treat venomous snake bites may have come from an unlikely source &ndash; stem cell research.</p>
<p>There are about 250 types of venomous snake species with the highest prevalence of snakebite envenoming in Africa, Asia, and Latin America. Snake venom is composed of multiple natural toxins, enzymes, proteins, and peptides, which act together to cause rapid tissue damage or death. The exact venom composition is incredibly diverse and species-dependent, making treatment highly specific for each snake species. Snake bites can be lethal or lead to life-long, chronic health problems, such as neurotoxicity and nerve-related paralysis, irreversible kidney damage after excessive renal bleeding, or limb amputation.</p>
<p><img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2020/11/snake-venom-figure-1.tmb-300×400-1.jpg” data-displaymode=”Thumbnail” alt=”Snake Venom Blog Figure 1″ title=”Snake Venom Blog Figure 1″ style=”float: left; margin-right: 10px;” />Most current treatments aim to neutralize the venom, such as antivenom. In general, antivenom is made by harvesting snake venom through manually milking the snake (see Figure 1 on left) and injecting small doses of the venom into donor animals, such as horses, to elicit an immune response and antibody production. These anti-venom antibodies are then injected into the snake bite victim where they selectively recognize and bind to structural components of the snake venom, neutralizing the toxins.</p>
<p>Making anti-venom in this way is time consuming, hard to scale up, and must be done individually for each species of venomous snake. According to the World Health Organization, many antivenom-manufacturers have ceased production in the last 20 years, causing reduced supply and drastically increased prices. Unfortunately, effective alternative therapeutic approaches are scarce.</p>
<p><strong><br />
<br />
Using Stem Cells to Fight Snake Bites</strong></p>
<p>Recently, scientists turned to stem cells to solve this problem. Researchers can use stem cells to grow three dimensional mini organs, called organoids, which maintain essential characteristics of the specific organ or tissue. For the first time, scientists tried to derive organoids from snake stem cells to see if they could grow <a href=”https://edition.cnn.com/2020/01/29/health/snake-venom-lab-organoids-stem-cell-scn/index.html”>venom-producing mini organs in the lab</a>. Researchers dissected venom glands of nine species of snake and successfully grew organoids from stem cells found in snake salivary glands (see Figure 2 on right).<img src=”https://www.closerlookatstemcells.org/wp-content/uploads/2020/11/snake-venom-figure-2.tmb-300×400-1.jpg” data-displaymode=”Thumbnail” alt=”Snake Venom Blog Figure 2″ title=”Snake Venom Blog Figure 2″ style=”float: right; margin-top: 10px; margin-bottom: 10px; margin-left: 10px;” /> </p>
<p><em>Figure 2: Snake venom gland organoids from the&nbsp;Aspidelaps&nbsp;lubricus&nbsp;snake. Credit: Ravian&nbsp;van&nbsp;Ineveld, Princess&nbsp;M&aacute;xima Center for Pediatric Oncology, the Netherlands</em>.<br />
<br />
Strikingly, these organoids contained cells that could secrete functionally active venom that exerted species-specific effects on neurons and muscle cells in the lab. Further, organoid-derived venom has similar composition to venom directly milked from snakes. Scientists are now hoping to establish a biobank, or repository, of snake gland organoids for all venomous snakes of medical relevance, in order to create an unlimited supply of venom.</p>
<p>Since publishing the initial research paper, Jens Puschhof says the group has already expanded the organoid repertoire to include a broader selection of venomous snakes. He added that &nbsp;using venom from organoids rather than milking snakes could help produce a safer, more reliable product, as there is variation in venom components of individual snakes. Next steps include using venom organoids to purify the toxic components and make antibodies in the lab, rather than in horses, to more efficiently manufacture antidotes and enhance global access.&nbsp; </p>
<p><strong>Can Snake Venom Treat Tumors?</strong></p>
<p>A biobank of snake venom organoids could potentially provide treatments for other diseases. The U.S. Food and Drug Administration (FDA) has previously approved drugs that are derived from snake venom for treating acute cerebral infarction, acute coronary syndrome, and as prophylaxis for hemorrhage during surgery. </p>
<p>Strikingly, early research indicates that peptides from snake venom may have antitumor effects. Components of snake venom called disintegrins, such as Contortrostatin from the snake <em>Agkistrodon contortrix contortrix</em>, can inhibit blood vessel formation and cancer cell adhesion in lab models of human metastatic skin cancer. Additional research indicates that a potent peptide found in venom could interfere with blood vessel formation, reducing delivery of nutrients to tumors in a mouse model of breast cancer. The availability of venom-biobanks would allow scientists to further study snake venom components to see if there are opportunities for biomedical innovation.</p>
<p><strong>The Bite</strong></p>
<p>Fifty people are bitten by a snake every five minutes, and one will die in this silent healthcare crisis. Novel stem cell research has allowed scientists to successfully grow mini venom-producing organoids&nbsp; in a petri dish, which may be used to develop accessible and affordable antivenom therapies. This scientific innovation of developing snake venom gland organoids has the potential to save people around the world from deadly snake bites and other diseases.</p>
<p><em>Blog by guest contributor Felix Buchner, Masters student </em><em>at the CRTD/TU Dresden in Germany.</em></p>
<p><em>Thank you to </em><em>the three graduate students in Hans Clevers&rsquo; lab at the Hubrecht Institute in the Netherlands, Jens Puschhof, Yoep Beumer, and Yorick Post who contributed to work shown in Figure 2.</em></p>

Closing in on Pluripotent Stem Cell Therapies for Liver Diseases

The liver, our largest internal organ, plays vital roles in food metabolism, energy storage, and elimination of toxins. Liver disorders kill more than two million people per year, representing a significant global health challenge. In addition, liver failure is the end stage of many life-threatening diseases, such as alcoholic hepatitis, Hepatitis B infection, and liver cancer. In such conditions, liver failure results from the widespread death of the major cell type of the liver, the hepatocyte.
<p style=”text-align: left;”>Organ transplantation is the only available therapeutic option for people with end-stage liver disease. However, because of difficulties in finding immune-matched donors, only around 10 percent of patients requiring a transplant receive a new functional liver, and many patients die before a suitable donor can be found. Researchers are looking to the potential of stem cell research to provide novel treatments to patients who do not have access to a liver transplant.</p>
<p style=”text-align: left;”><a href=”https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/”>Pluripotent stem cells</a> can become any cell type in the body. These stem cells can be grown in the lab in large numbers and can be transformed into functional cells with the goal that they will be able to integrate into a human organ and successfully carry out physiological activities or even potentially replace the need for donated organs for transplantation.</p>
<p style=”text-align: left;”>Scientists have been working towards the production of functional liver cells for more than 20 years. After great effort, scientists determined how to mimic the various stages of embryonic liver development in the laboratory to produce stem cell-derived hepatocytes that are comparable to normal liver cells, in terms of food metabolism, energy storage, and elimination of toxins. Scientists are studying whether these stem cell-derived liver cells can safely be transplanted into a patient or used to create an artificial liver that would function outside of the body.&nbsp;&nbsp;</p>
<p style=”text-align: left;”>Recently, a group led by Mureo Kasahara at the National Center for Child Health and Development in Japan <a href=”https://medicalxpress.com/news/2020-05-japan-newborn-liver-stem-cells.html”>treated a six-day-old baby</a> with pluripotent stem cell-derived hepatocytes for the first time. This newborn suffered a rare genetic urea cycle disorder where the liver cannot eliminate ammonia, resulting in the accumulation of this toxic compound in the baby&rsquo;s blood. This disease normally requires a liver transplantation, but this complex surgery is too dangerous until about three to six months.</p>
<p style=”text-align: left;”>To &ldquo;bridge&rdquo; the patient until the time when the baby could safely receive a liver transplant, doctors decided to try a novel stem cell treatment. Doctors injected stem cell-derived hepatocytes into the baby&rsquo;s liver with the hope of providing temporary support until a transplant was feasible. Strikingly, after the stem cell treatment, the level of ammonia in the blood stabilized, allowing the baby to survive until five months of age. The baby then received a successful liver transplant from the father and is now healthy and home from the hospital. While further studies are required to test the safety and efficacy of this procedure, it is a promising finding that the transplanted stem cell-derived hepatocytes appeared to bridge the baby&rsquo;s liver function until transplantation was possible.</p>
<p style=”text-align: left;”>Researchers also are exploring ways that stem cell-derived liver cells might help patients through external devices. As an alternative to transplantation, stem cell-derived hepatocytes can be used to create a dialysis-like device that treats liver disease by clearing blood toxins. Such a machine, also known as a bioartificial liver, may ease the symptoms of liver failure and prolong the time until a liver transplant is needed.</p>
<p style=”text-align: left;”>&ldquo;We are currently using these stem cell-derived hepatocytes to devise a bioartificial liver system to treat liver failure patients,&rdquo; said Dr Xiaolei Shi, chief hepatobiliary surgeon at the Drum Tower Hospital of Nanjing University, China.</p>
<p style=”text-align: left;”>Shi and colleagues used stem cell-derived hepatocytes to make &ldquo;mini liver tissues,&rdquo; called hepatic spheroids. In pre-clinical studies, these spheroids were used to create a bioartificial liver that was able to rescue pigs from severe liver failure. This is a significant result because pigs are comparable in size and weight to humans and therefore offer insight into how these machines may function in human patients. This research is important pre-clinical support for going forward with clinical trials in humans, which will thoroughly test whether the bioartificial liver is safe and effective for treating liver disease.</p>
<p style=”text-align: left;”>While there has been significant progress, challenges remain. There are ongoing concerns whether stem cell therapy might form tumors following transplantation. External devices, however, physically separate stem cell derivatives from the patient, which could circumvent certain safety issues as the cells can easily be removed if issues arise.</p>
<p style=”text-align: left;”>Recent advances shed light on the ways that stem cell-derived liver cells might be used to help patients with various types of liver diseases. Ongoing research will continue to explore how pluripotent cell therapies can safely be used to help treat millions suffering worldwide. </p>
<p style=”text-align: left;”>_________________________________________________</p>
<p style=”text-align: left;”>Blog by guest contributor S.C. Jacky Sun, PhD candidate in the labs of Ed Stanley and Andrew Elefanty at the Murdoch Children&rsquo;s Research Institute, Melbourne.</p>

Scientists Use Stem Cells to Uncover COVID-19 Effects on the Heart

Scientists and medical professionals worldwide are collaborating to discover how to address the coronavirus pandemic and to better understand its effects on the body. It is well known that COVID-19 can devastate the lungs, causing symptoms including cough, shortness of breath, pneumonia, and acute respiratory distress syndrome<a href=”https://isscresearch-my.sharepoint.com/personal/jperlin_isscr_org/Documents/A%20closer%20look/Blog%202020/September%20-%20COVID%20and%20stem%20cells/ACL%20Sept%202020%20Blog%20Arun%20Sharma%20final.docx#_ENREF_2″ title=”Madjid, 2020 #5″></a>. However, there is mounting evidence that the coronavirus may directly or indirectly infect other cell types as well. Of particular interest is how the coronavirus affects the heart. About 20-30% of patients hospitalized with COVID-19 have cardiac injury, such as arrythmia, inflammation of the heart, or heart attack, which is associated with higher risk of death. Those that recover from COVID-19 can exhibit cardiac dysfunction for months afterwards, even if they exhibited only mild COVID-19 symptoms. Researchers are using stem cell models to study coronavirus infection in the lab to determine how different cell types in the body are affected. </p>
<p>An important question to address is whether cells are indirectly or directly infected by the coronavirus. In the cardiovascular system, heart cells may be injured indirectly by a lack of oxygen supply to the heart due to COVID-19&rsquo;s impact on the lungs, or the virus may directly infect heart muscle and associated blood vessels. Direct damage to the heart muscle cells could lead to heart rhythm problems or heart failure, while direct damage to blood vessel cells could impair circulation. Insight into the infection process and the resulting impact can improve our understanding of the disease and lead to the development of safe and effective treatment options. </p>
<p>Initial clinical studies indicate that coronavirus infection can directly cause injury to the heart, resulting in a dangerous condition known as myocarditis, a condition where immune cells are hyperactivated in the heart muscle. Otherwise healthy individuals who are infected with coronavirus can exhibit this inflammation of the heart, which in severe cases can lead to cardiac arrest. Even high-level college athletes have been observed to develop myocarditis after coronavirus infection. <a href=”https://www.nytimes.com/2020/08/23/sports/ncaafootball/college-football-myocarditis-coronavirus.html?auth=login-email&amp;login=email”>Initial reports</a> indicate that about 15% of these athletes that recovered from COVID-19 showed signs of myocarditis, whether or not they ever showed COVID-19 symptoms. </p>
<p>To address whether coronavirus indirectly or directly infects different cells in the body scientists can use human <a href=”https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/#induced-pluripotent”>induced pluripotent stem cells</a> (hiPSCs), which are made from a small sample of skin or blood. These are powerful stem cells that can be transformed into various cell types and then infected with the coronavirus in order to study the infection process and the resulting effects on the body. Using this method, researchers have shown that both stem cell-derived heart muscle cells and blood vessels are directly susceptible to coronavirus infection. This is not true of cells in all tissues. &nbsp;Some types of brain tissue, for example, cannot be directly infected by the coronavirus. These laboratory studies parallel clinical reports that some tissues are more susceptible to coronavirus infection than others.</p>
<p>Scientists found that after stem cell-derived heart muscle cells were infected with coronavirus, some cells stopped beating and died within three days. Infection also led to an immune response and an attempt to alleviate the viral infection. Researchers can now use these infected heart cells to screen for drugs that can improve their function and survival. These cells could also be used to identify new antiviral drugs that could directly and specifically reduce coronavirus replication in the heart, potentially reducing cardiac injury and limiting the spread of the virus. Scientists are also using the cells to study COVID-induced myocarditis by adding immune cells to their experiments.</p>
<p>The extent and conditions in which the coronavirus impacts the heart and blood vessels is becoming more clear as scientists learn more about the virus using these human iPSC models. However, better clinical data is needed to understand the different ways that infection directly and indirectly affects the cardiovascular system in patients. Human iPSC models could help identify potential new treatments that could alleviate both of these types of cardiovascular complications, leading to better outcomes for COVID-19 patients<em>. </em>Stem cell models are a valuable ally to the global stem cell research community, which is working collaboratively on many fronts to fight coronavirus and COVID-19. </p>
<p>Blog by guest contributor Arun Sharma, PhD, postdoctoral fellow in the lab of Clive Svendsen, PhD at Cedars Sinai, CA, USA.&nbsp;&nbsp;</p>