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Researchers create embryo-like structures from monkey embryonic stem cells

Source: Cell Press
Date: 4/6/2023
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Human embryo development and early organ formation remain largely unexplored due to ethical issues surrounding the use of embryos for research as well as limited availability of materials to study. In a paper published April 6 in the journal Cell Stem Cell, a team of investigators from China report for the first time the creation of embryo-like structures from monkey embryonic stem cells. The investigators also transferred these embryo-like structures into the uteruses of female monkeys and determined that the structures were able to implant and elicit a hormonal response similar to pregnancy.

“The molecular mechanisms of human embryogenesis and organogenesis are largely unclear,” says co-corresponding author Zhen Liu of the Chinese Academy of Sciences (CAS) in Shanghai. “Because monkeys are closely related to humans evolutionarily, we hope the study of these models will deepen our understanding of human embryonic development, including shedding light on some of the causes of early miscarriages.”

“This research has created an embryo-like system that can be induced and cultured indefinitely,” says co-corresponding author Qiang Sun, also of CAS. “It provides new tools and perspectives for the subsequent exploration of primate embryos and reproductive medical health.”

The investigators started with macaque embryonic stem cells, which they exposed to a number of growth factors in cell culture. These factors induced the stem cells to form embryo-like structures for the first time using non-human primate cells.

When studied under a microscope, the embryo-like structures, also called blastoids, were found to have similar morphology to natural blastocysts. As they further developed in vitro, they formed arrangements that looked like the amnion and yolk sac. The blastoids also started to form the types of cells that eventually make up the three germ layers of the body. Single-cell RNA sequencing revealed that the different types of cells found within the structures had similar gene expression patterns to cells found in natural blastocysts or post-implantation embryos.

The blastoids were then transferred into the uteruses of 8 female monkeys; in 3 of the 8, the structures implanted. This implantation resulted in the release of progesterone and chorionic gonadotropin, hormones normally associated with pregnancy. The blastoids also formed early gestation sacs, fluid-filled structures that develop early in pregnancy to enclose an embryo and amniotic fluid. However, they did not form fetuses and the structures disappeared after about a week.

In future work, the investigators plan to focus on further developing the system of culturing embryo-like structures from monkey cells. “This will provide us with a useful model for future study,” says co-corresponding author Fan Zhou of Tsinghua University. “Further application of monkey blastoids can help to dissect the molecular mechanisms of primate embryonic development.”

The researchers acknowledge the ethical concerns surrounding this type of research but emphasize that there are still many differences between these embryo-like structures and natural blastocysts. Importantly, the embryo-like structures do not have full developmental potential. They note that for this field to advance it’s important to have discussions between the scientific community and the public.

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Studying the Neanderthal DNA found in modern humans using stem cells and organoids

Source: Cell Press
Date: 6/18/2020
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Protocols that allow the transformation of human induced pluripotent stem cell (iPSC) lines into organoids have changed the way scientists can study developmental processes and enable them to decipher the interplay between genes and tissue formation, particularly for organs where primary tissue is not available. Now, investigators are taking this technology and applying it to study the developmental effects of Neanderthal DNA. The findings are reported June 18 in the journal Stem Cell Reports.

“Using iPSC lines to study the functions of archaic human DNA is an untapped but very interesting approach,” says senior author J. Gray Camp of the Max Planck Institute for Evolutionary Anthropology in Germany and the University of Basel in Switzerland. “No one has ever been able to look at the role Neanderthal DNA plays during development.”

Studies have found that about 2% of the genomes of modern humans from outside Africa are composed of Neanderthal DNA. This archaic DNA is a result of mating between the two groups tens of thousands of years ago.

In the new study, the team used resources from the Human Induced Pluripotent Stem Cells Initiative (HipSci), an international consortium that provides data and cell lines for research. Nearly all of the data and cell lines in HipSci are from people of UK and Northern European descent. The researchers analyzed this cell line resource for its Neanderthal DNA content and annotated functional Neanderthal variants for each of the cell lines.

“Some Neanderthal alleles have relatively high frequency in this population,” Camp explains. “Because of that, this iPSC resource contains certain genes that are homozygous for Neanderthal alleles, including genes associated with skin and hair color that are highly prevalent in Europeans.”

Camp’s team used five cell lines to generate brain organoids and generated single-cell RNA sequencing data to analyze their cell composition. They showed that this transcriptomic data could be used to track Neanderthal-derived RNA across developmental processes. “This is a proof-of-principal study showing that you can use these resources to study the activity of Neanderthal DNA in a developmental process,” Camp says. “The real challenge will be scaling up the number of lines in one experiment, but this is already starting to be possible.”

Camp notes that this research could be expanded to study other ancient human populations, including Denisovans, which have genes that are present primarily in Oceanian populations. His team also plans to continue studying Neanderthal alleles using HipSci and other resources. “Organoids can be used to study a number of different developmental processes and phenotypes controlled by Neanderthal DNA, including the intestinal tract and digestion, cognition and neural function, and the immune response to pathogens,” he concludes.

The researchers have generated a web browser with this information to make the data easily accessible for future research.

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A new way of thinking about tau kinetics, an essential component of Alzheimer’s disease

Source: Cell Press
Date: 03/21/2018
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Alzheimer’s disease is most often characterized by two different pathologies in the brain: plaque deposits of a protein called beta-amyloid and tangles of another protein called tau. A paper appearing March 21 in the journal Neuron brings new insights into how tau proteins are processed in the human central nervous system. Researchers found that tau production and secretion from nerve cells appears to be an active process in the natural course of Alzheimer’s disease. This may explain why experimental treatments targeting tau have had disappointing results, as the current focus of these drugs assumes that the protein is primarily released from dying nerve cells.

“This study changes our way of thinking about tau in the context of neurodegenerative diseases,” says senior author, Randall Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis. “Contrary to the idea that tau is a product released by dying neurons, we have shown that the release of tau is an active and controlled activity that appears to be an important part of the disease process.”

In the study, the investigators used mass spectrometry and a method called stable isotope labeling kinetics to study tau in the cerebrospinal fluid (CSF) of people who were known to have Alzheimer’s and healthy controls. This enabled them to measure the tau turnover rate and its half-life in the human nervous system as well as to analyze the different forms of the protein. Their findings revealed that certain forms of tau have faster turnover rates than others, suggesting that they may have unique biological activities. In addition, they found that production rate of tau was higher in people with Alzheimer’s, suggesting a biological link between the presence of amyloid plaques and tau kinetics.

“We’ve known for a long time that CSF tau is increased in Alzheimer’s disease, but until this study, we didn’t know if tau production was increased or if clearance was decreased,” says Chihiro Sato, a member of the Bateman lab and one of the paper’s co-first authors. “Our results showing that tau production is increased suggest that we might want to target tau production therapeutically.”

The researchers also looked at tau production in human neurons made from induced pluripotent stem cells (iPSCs). “The research with the iPSCs was really valuable, because we were able to ask questions about human neurons that we wouldn’t be able to ask in living subjects,” says Celeste Karch, an Assistant Professor of Psychiatry at Washington University School of Medicine and one of the study’s co- authors. “We found that inside neurons some forms of tau are turned over more quickly than others. Interestingly, the forms of tau that are turned over more quickly are also those that are prone to misfold and aggregate in the context of Alzheimer’s disease and other tauopathies.”

“Using mass spectrometry, we found that tau is truncated in CSF in healthy people and Alzheimer’s patients,” says Nicolas Barthélemy, a member of the Bateman lab and the other co-first author. “Truncated tau is released differently from full-length tau, supporting our hypothesis that tau is actively processed under physiological and pathological conditions.”

The investigators say the knowledge gained from this study not only helps to understand more about Alzheimer’s disease, but other diseases characterized by the aggregation of tau as well. “We expect these findings will help us to distinguish between Alzheimer’s and other types of tauopathies in future,” Bateman says. The investigators plan to expand their research to patients with some of these other diseases, including progressive supranuclear palsy and corticobasal degeneration, to determine whether there are different forms of tau in the cerebrospinal fluid and different kinetics underlying the changes that are observed.

“It’s hard to do clinical research on tauopathies right now, because we don’t have good tests for diagnosing these other diseases, such as frontotemporal dementia,” Bateman adds. “Having an accurate diagnosis helps not only in the clinic but also in clinical trials, to ensure that we’ve included the right patients in our studies.”

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How Stem Cells Decide Their Fate

Source: Memorial Sloan Kettering - On Cancer
Date: 08/13/2019
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Stem cells are defined by their ability to differentiate into other, more specialized cell types. When one stem cell divides into two (which are then called daughter cells), three things can happen to the new cells: Both cells can continue being stem cells, both cells can differentiate into a new cell type, or the cells can go their separate ways, with one maintaining the properties of a stem cell and the other becoming something new.

“It may be surprising, but as much as stem cells have been studied, we don’t know much about how they make this commitment when they divide,” says Michael Kharas, who is in the Sloan Kettering Institute’s Molecular Pharmacology Program. Dr. Kharas led a team from SKI, in collaboration with investigators at Weill Cornell Medical College, that discovered new details about how dividing stem cells choose what to become. Their findings were published August 13 in Cell Reports.

Dr. Kharas’s lab uses human and mouse blood (hematopoietic) stem cells to study how certain types of leukemia develop.

Knocking Out an Important Protein

When both daughter cells are the same cell type, this is called symmetric division. That’s true whether they continue being stem cells or become something new. When one cell stays a stem cell and the other differentiates, it’s called asymmetric division. This happens about 30 percent of the time.

“The beauty of asymmetric division is that you’re maintaining your stem cell numbers,” Dr. Kharas explains. “If every time a stem cell divides, it loses its identity as a stem cell, you will eventually deplete all the stem cells. But if all the cells remain stem cells, you’ll never get the variety of cell types you need to form an entire blood system.”

Previous work in the Kharas lab has focused on a protein called MUSASHI-2. The researchers found that when MUSASHI-2 is knocked out in blood stem cells, the cells lose their “stemness.” They are more likely to differentiate and become nonstem cells. Additionally, they have less of the asymmetric type of division.Targeting RNA-binding proteins has been identified as a new approach in the development of drugs for leukemia.

In the new study, the investigators — led by first authors Yuanming Cheng and Hanzhi Luo, of Dr. Kharas’s lab, and Franco Izzo from Weill Cornell — focused on a different protein: METTL3. Both MUSASHI-2 and METTL3 are RNA-binding proteins, but the METTL3 protein is the key enzyme that can add chemicals called methyl groups to specific RNA nucleotides. This process is called methylation, and it decorates RNA with marks called m6A. 

Ultimately, this helps regulate the stability of the RNAs and the efficiency of protein production. Targeting RNA-binding proteins has been identified as a new approach in the development of drugs for leukemia.

Taking a Closer Look at Stem Cells

To study the role of m6A, the researchers compared the blood-forming systems of mice that had METTL3 knocked out and those that did not, to see how blood development was affected. They found that the mice without the protein seemed to have an accumulation of blood stem cells, suggesting that the cells were unable to become more specialized cells. 

To get a better look at what was going on, the lab of Dan Landau at Weill Cornell studied the cells with a type of analysis called single-cell RNA sequencing (RNA seq). RNA seq enables researchers to determine which genes are being expressed, or turned on, in cells. This revealed that there were actually fewer stem cells than originally thought. But some of the cells seemed to be stuck in an intermediate state between stem cell and differentiated cell that the scientists had never seen before.

“These stem cells had reduced ability to symmetrically differentiate. Based on these findings, we believe that METTL3 — and therefore, RNA methylation — controls this specific type of division in hematopoietic stem cells,” Dr. Kharas notes. “This research suggests a general mechanism for RNA methylation in controlling how stem cells regulate their fate when they divide.”

Implications for Cancer Treatment and Beyond

Dr. Kharas explains that there are two main implications for this new finding.

Many researchers and pharmaceutical companies are focused on developing new leukemia drugs that target the RNA methylation process. “It’s important to know how these drugs might work and what unintended consequences they may have,” he says.

But perhaps more interesting to the researchers who worked on the project are the implications for understanding the division and differentiation of hematopoietic stem cells.

“Now that we have identified this new population of cells in our lab, we may be able to use them as a model to understand the intricate steps that happen when a stem cell decides to differentiate,” Dr. Kharas concludes. “It may eventually provide a new approach for growing large numbers of stem cells for the development of cell therapies.”

Dr. Kharas is a scholar of the Leukemia and Lymphoma Society. The MSK team was funded by a National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Career Development Award, an NIH/NIDDK grant (R01-DK101989-01A1), an NIH/National Cancer Institute grant (1R01CA193842-01), a Kimmel Scholar Award from the Sidney Kimmel Foundation, a V Scholar grant from the V Foundation for Cancer Research, a Geoffrey Beene Award from the Geoffrey Beene Cancer Research Center at MSK, an Alex’s Lemonade Stand ‘A’ Award Grant, and funding from the Starr Cancer Consortium. Dr. Luo is supported by a New York State Stem Cell Science training award. The Weill Cornell team received funding from a Burroughs Wellcome Fund Career Award for Medical Scientists, an American Society of Hematology Scholar Award, and the Leukemia and Lymphoma Society Translational Research Program.

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Salk team reveals clues into early development of autism spectrum disorder

Source: Salk Institute
Date: 01/07/2019
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Neurons from people with autism exhibit different patterns of growth and develop at a faster rate

Autism spectrum disorder (ASD) is a relatively common developmental disorder of communication and behavior that affects about 1 in 59 children in the US, according to the Centers for Disease Control and Prevention. Despite its prevalence, it is still unclear what causes the disease and what are the best ways to treat it.

Researchers at the Salk Institute compared stem cells created from individuals with ASD against stem cells created from those without ASD to uncover, for the first time, measurable differences in the patterns and speed of development in the ASD-derived cells.

The findings, published January 7, 2019, in the journal Nature Neuroscience, could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place.

“Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD,” says Salk Professor Rusty Gage, the study’s senior author and president of the Institute. “We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders.”

For the study, the researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells—cells that have the ability to develop into any cell type. They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors.

By using molecular “snapshots” from different developmental stages in the stem cells, the team was able to track genetic programs that switched on in a certain order as the stem cells developed into neurons. This revealed key differences in the cells derived from people with ASD. For instance, the Salk team observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD. This genetic program includes many genes that have been associated with higher chances of ASD. In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group.

“It’s currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred,” says first author Simon Schafer, a postdoctoral fellow in the Gage lab. “A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development.”

“This is a very exciting finding, and it encourages us to further refine our methodological framework to help advance our understanding of the early cell biological events that precede the onset of symptoms,” adds Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. “Studying system dynamics could maximize our chance of capturing relevant mechanistic disease states.”

The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression.

They next plan to focus on the creation of brain organoids, three-dimensional models of brain development in a dish that enable scientists to study the interactions between different types of brain cells.

“The current diagnostic methods are mostly subjective and occur after the emergence of behavioral abnormalities in young children,” Schafer says. “We hope these studies will serve as a framework for developing novel approaches for diagnosis during an early period of child development—long before behavioral symptoms manifest—to have the maximum impact on treatment and intervention.”

Other researchers on the paper were Apua C. M. Paquola, Shani Stern, Monique Pena, Thomas J. M. Kuret, Marvin Liyanage, Abed AlFatah Mansour, Baptiste N. Jaeger, Maria C. Marchetto and Jerome Mertens of Salk; David Gosselin of Université Laval in Quebec City, Canada; Manching Ku of the University of Freiburg in Freiburg, Germany; and Christopher K. Glass of the University of California San Diego.

This work was funded by The James S. McDonnell Foundation, G. Harold & Leila Y. Mathers Charitable Foundation, JPB Foundation, the March of Dimes Foundation, National Institutes of Health (NIH) grants MH095741 and MH090258, The Engman Foundation, Annette C. Merle-Smith, The Paul G. Allen Family Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust. It was also supported by NIH grant P30 014195, the German Research Foundation (DFG) and the Chapman Foundation.

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Research confirms nerve cells made from skin cells are a valid lab model for studying disease

Source: Salk Institute
Date: 01/15/2019
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Salk and Stanford team shows that induced neuronal cells derived from fibroblasts are similar to neurons in the brain, on the epigenomic level

The incidence of some neurological diseases—especially those related to aging, such as Alzheimer’s and Parkinson’s diseases—is increasing. To better understand these conditions and evaluate potential new treatments, researchers need accurate models that they can study in the lab.

Researchers from the Salk Institute, along with collaborators at Stanford University and Baylor College of Medicine, have shown that cells from mice that have been induced to grow into nerve cells using a previously published method have molecular signatures matching neurons that developed naturally in the brain.

The study, published in eLife on January 15, 2019, opens the door for better ways to model an individual patient’s disease. This technique would enable researchers to study how neurological conditions develop, as well as to test new therapies. The new technology also could help to advance research into gene therapies that are derived from a patient’s own cells.

“This research is charting the path for the most optimal way of creating neurons in the lab,” says Salk Professor Joseph Ecker, one of the study’s two senior authors. “By taking these cells and reprogramming them into neurons, you can potentially learn new things about how these diseases function on a cellular level, especially diseases driven by genetic changes.”

The cells used in the study, called fibroblasts, make up most of the connective tissue in animals and play an important role in wound healing. Researchers have been studying how to transform fibroblasts into neuron cells in laboratory dishes, but until now they didn’t know whether these newly created neurons accurately corresponded to neurons that had grown naturally in the brain.

The technique for inducing the fibroblasts to grow into neurons with the matching epigenome was developed by Stanford’s Marius Wernig, the paper’s co-senior author. With this method, making induced neuronal cells does not involve pluripotent intermediates. Instead, the cells are directly converted from fibroblasts to neurons.

“An important question in cellular engineering is how to know the quality of your product,” says co-first author Chongyuan Luo, a postdoctoral fellow in Ecker’s lab. “If we’re making neurons from fibroblasts, we want to know how they compare with neurons in the brain. We are particularly interested in looking at these cells at the level of the epigenome.”

The epigenome is made up of chemicals that attach to DNA and regulate when genes get turned on and translated into proteins. Differences between the epigenomes of induced and naturally grown neurons could result in different features of induced neurons that might make them less accurate models of neuronal behavior.

Using a technique developed in the Ecker lab called MethylC-seq, the researchers looked at every place in the genome where chemical groups called methyl groups are attached. They confirmed that these induced neurons have epigenomes that match neurons in the brain.

“This research was done in mouse cells, but we plan to use the same technology to study induced neurons made with human cells,” explains Ecker, who is director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. Ecker plans to also collaborate with colleagues to apply the technology to look at human cells to better understand age-related cognitive decline.

Other researchers on the paper were Rosa Castanon and Joseph R. Nery of Salk; Sean M. Cullen and Margaret A. Goodell of Baylor College of Medicine; and Qian Yi Lee, Orly L. Wapinski, Moritz Mall, Michael S. Kareta and Howard Y. Chang of Stanford.

The work was supported by the National Institutes of Health (grants P50-HG007735 and R01 DK092883), the California Institute for Regenerative Medicine (grant RB5-07466) and the Howard Hughes Medical Institute.

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Study examines direct-to-consumer stem cell clinics in 6 Southwestern states

Source: Cell Press
Date: 08/01/2019
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This direct-to-consumer stem cell marketplace has come under increasing scrutiny, but relatively little is known about the clinics that deliver these treatments or how the treatments they offer align with the expertise of the practitioners providing them. In a paper published August 1 in the journal Stem Cell Reports, investigators offer a detailed characterization of nearly 170 stem cell businesses across six southwestern states. The study focused on Arizona, California, Colorado, Nevada, New Mexico, and Utah, where the researchers estimate that about one-third of all stem cell clinics in the US are located.

“Previous studies have built up a broad picture of the direct-to-consumer stem cell industry,” says Emma Frow, an assistant professor in the School for the Future of Innovation in Society and the School of Biological and Health Systems Engineering at Arizona State University, co-first author on the paper along with David Brafman, also an assistant professor of bioengineering at Arizona State University.

“We took a deeper dive into a smaller number of clinics and found that there’s a lot of variation among the businesses offering these services,” she says. “About 25% focus exclusively on stem cells, but many others are facilities like orthopedic and sports medicine clinics that have added stem cells to their roster of services on offer. For these clinics, it’s very difficult to know how much of their business comes from stem cell treatments.”

The researchers conducted extensive online searches for stem cell clinics in the six states. “There’s no exhaustive list of all the clinics that exist,” Frow says. “This is a lively marketplace, with businesses opening and closing and changing their names.” For the 169 businesses they identified, they catalogued the treatments being offered, the medical conditions these clinics purported to treat, and the types of cells they claimed to use. For the 25% of clinics focused solely on stem cells, they also looked at the stated expertise of the care providers at these clinics in relation to the medical conditions they offer to treat with stem cells.

The researchers found that orthopedic, inflammatory, and pain conditions were the main types of medical conditions treated with stem cells at direct-to-consumer stem cell clinics in the Southwest. Frow notes that these types of conditions “tend to be chronic problems that often are not curable. The market has really capitalized on targeting conditions that are hard to manage with existing therapies.”

Earlier studies have shown a lower percentage of clinics treating inflammatory conditions. “This could mean that the number of clinics treating inflammatory conditions is on the rise or that, in the Southwest, there is more focus on treating inflammatory conditions than in other parts of the US,” Frow suggests.

The researchers also found differences in the degree to which the listed expertise of care providers at stem cell clinics matched the medical conditions they treat with stem cells. For example, they identified that specialists in orthopedics and sports medicine were more likely to restrict stem cell treatments to conditions related to their medical specialties, while care providers listing specialties in cosmetic or alternative medicine were more likely to treat a much wider range of conditions with stem cells.

Public discussions of direct-to-consumer stem cell treatments usually treat clinics as though their business models were all similar, but this study highlights some key differences across these clinics. “We think it makes a difference whether a business is focused solely on stem cells or offers it as one treatment among many,” Frow says. “And we think it’s important to pay attention to the medical qualifications and expertise of the care providers offering stem cell treatments. Just because someone is board certified doesn’t necessarily mean they are qualified to provide stem cell treatments. You really need to ask what they are board certified in and whether their medical expertise is well-matched to the condition you are seeking treatment for.”

Recent moves by the FDA to tighten up its guidelines and restrict the practices of these clinics have generated a lot of attention. The authors of this study see their work as contributing to these discussions. “We want to bring more transparency to discussions of the direct-to-consumer stem cell marketplace and to empower consumers to figure out what kinds of questions to ask when they’re considering treatment,” Frow says. “We also want to help the scientific community get a better understanding of the situation and to help the FDA and state medical boards think through their priorities with regards to regulating the market.”

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This research was funded by the Lincoln Center for Applied Ethics and the Institute for Social Science Research at Arizona State University.

Stem Cell Reports, Frow and Brafman et al.: “Characterizing direct-to-consumer stem cell businesses in the Southwest United States.” https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(19)30253-X

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Researchers Discover Stem Cells That May Drive Aggressive Behavior in Glioblastoma

Source: Memorial Sloan Kettering - On Cancer
Date: 02/20/2020
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For the past several years, researchers have recognized that the brain tumor glioblastoma is powered by cancer cells called tumor stem cells. Figuring out how tumor stem cells function is important because their ability to survive likely explains why glioblastoma is so hard to treat.

A multicenter team led by scientists at Memorial Sloan Kettering recently reported discovering a likely identity for these tumor stem cells. The leading contenders are called radial glia cells. Radial glia cells play a key role in building fetal brains but were previously thought to disappear after birth. The findings were published January 30 in Stem Cell Reports.

“We can’t say with certainty that radial glia cells are the same as tumor stem cells, but they are now very high on the candidate list,” says physician-scientist Viviane Tabar, Chair of MSK’s Department of Neurosurgery, who was the study’s senior author. “The look and behavior of brain stem cells in the developing brain and the tumor stem cells that we have identified are so similar to each other. This is the first time we’ve seen these features in cells from a human tumor.”

An Unexpected Finding

The first clues about the identity of these tumor stem cells were uncovered by Rong Wang, a research associate in Dr. Tabar’s lab. Dr. Wang was studying tumor tissue that had been removed from patients. She was using the tissue to grow organoid-like structures in petri dishes. Organoids are miniature organs that look and behave very much like their full-size counterparts. They are an increasingly important tool across cancer research for studying tumor development as well as for testing drugs.

Dr. Wang noticed that some cells in the organoids had an unusual shape and exhibited unusual behavior. They had very long processes, or tails, and when they divided, their daughter cells had the same shape. Additionally, when these unusual cells divided, their nuclei jumped over long distances. Dr. Wang recognized that these features are also seen in radial glia.

Further analysis confirmed that these unusual cells also were present in the tissue taken from patients: The team studied samples from dozens of tumors.

“Radial glia cells previously were not thought to persist in adulthood,” Dr. Tabar explains. “If glioblastoma tumors arise from them, that may mean that humans retain some radial glia cells in our brains as adults. The other possibility is that the genetic changes in the cancer turn some of the brain cells back into cells that look very much like radial glia cells.”

A Valuable Collaboration

To learn more about these cells, the Tabar lab collaborated with Dana Pe’er, Chair of the Sloan Kettering Institute’s Computational and Systems Biology Program, as well as with computational biologists at the Wellcome Sanger Institute in the United Kingdom.

They performed studies called single-cell RNA sequencing to look at which genes were expressed, or turned on, in individual cells. The patterns of gene expression observed in the samples taken from patient tumors and those grown in the lab were very similar to what’s seen in radial glia cells from embryos.

“This was a very challenging study to pull together. We took advantage of MSK’s wide range of tumors and access to fresh surgical tissue, as well as the resources of the Computational and Systems Biology Program here,” Dr. Tabar says.

A Potential Explanation for a Cancer’s Aggressive Behavior

Additional research is needed to confirm whether these cells are indeed the same. Another focus of future work will be the role of inflammation. “Inflammation may help bring radial glia-like cancer cells out of dormancy,” Dr. Tabar explains. “This could explain why inflammation can sometimes lead to the worsening of brain tumors.”

Dr. Tabar hopes that the publication of the findings will encourage further analysis and that “as technology advances, there will be easier ways to identify and study these cells,” she concludes.

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Snake stem cells used to create venom-producing organoids

Source: Cell Press
Date: 01/23/2020
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Organoids have become an important tool for studying many disease processes and testing potential drugs. Now, they are being used in a surprising and unexpected way: for the production of snake venom. On January 23 in the journal Cell, researchers are reporting that they have created organoids of the venom glands of the Cape coral snake (Aspidelaps lubricus cowlesi) and that these glands are capable of producing venom.

“More than 100,000 people die from snake bites every year, mostly in developing countries. Yet the methods for manufacturing antivenom haven’t changed since the 19th century,” says senior author Hans Clevers of the Hubrecht Institute for Developmental Biology and Stem Cell Research at Utrecht University in the Netherlands. “It’s clear there is a huge unmet medical need for new treatments.”

He adds: “Every snake has dozens of different components in their venom. These are extremely potent molecules that are designed to stop prey from running away. They affect systems as varied as the brain, neuromuscular junctions, blood coagulation, and more. Many of them have potential bioprospecting applications for new drugs.”

Clevers’ lab traditionally focuses on organoids made from human and mouse cells. But some of his students decided to study stem cells and develop organoids from reptiles. “This is a field that does not exist, so they thought it was interesting to study the most iconic reptilian organ, the snake venom gland,” he says. “Once we grew the venom glands as organoids, we realized that they make a lot of venom.”

The investigators started with the Cape coral snake because they knew a breeder who was able to supply some fertilized eggs. The snakes were removed from the eggs before hatching, and small pieces of tissue were removed from various organs and placed into gels, along with growth factors. In addition to the venom glands, the researchers also made organoids of the snake liver, pancreas, and gut.

“It would have been difficult to isolate stem cells from these snakes because we don’t know what they look like,” Clevers explains. “But it turned out we didn’t need to. The cells soon began dividing and forming structures.” In fact, he says, the venom gland organoids grew so fast that in just one week, they were able to break them apart and re-plate them, generating hundreds of plates within two months. He notes that if it could be commercialized, this method would be much more efficient than the way venom is currently produced–by raising snakes on farms and milking their glands.

The researchers were able to identify at least four distinct types of cells within the venom gland organoids. They confirmed that the venom peptides produced were biologically active and resembled the components of venom from live snakes.

A challenge of the work was determining gene-expression levels in the venom gland organoids. “The genomes of most snakes have not been annotated,” Clevers says. The investigators were able to identify certain genes that were active under expansion conditions, suggesting that these pathways–including most importantly the Wnt pathway–may play a role in reptilian stem cell growth.

One of the collaborators on the study was Freek Vonk, a herpetologist and well-known Dutch television host who Clevers calls “the Steve Irwin of Holland.” Vonk is affiliated with Leiden University and the Naturalis Biodiversity Center.

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This study was funded by ALS foundation Netherlands, a Sir Henry Dale Fellowship, the Wellcome Trust, and the Royal Society. Clevers is inventor on several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. Two of the study’s authors are employees of MIMETAS BV, the Netherlands, which is marketing the OrganoPlate. OrganoPlate is a registered trademark of MIMETAS.

Cell, Post et al.: “Snake Venom Gland Organoids” https://www.cell.com/cell/fulltext/S0092-8674(19)31323-6

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Bioethicist calls out unproven and unlicensed ‘stem cell treatments’ for COVID-19

Source: Cell Press
Date: 05/07/2020
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As the COVID-19 pandemic enters its third month, businesses in the United States are marketing unlicensed and unproven stem-cell-based “therapies” and exosome products that claim to prevent or treat the disease. In Cell Stem Cell on May 5, bioethicist Leigh Turner describes how these companies are “seizing the pandemic as an opportunity to profit from hope and desperation.”

“I’m concerned that individuals purchasing these supposed ‘therapies’ for COVID-19 will be scammed,” says Turner (@LeighGTurner), an associate professor at the University of Minnesota Center for Bioethics. “I’m also worried that they’ll be injured as a result of being given products that haven’t been adequately tested, or that they’ll forgo measures like social distancing because they’ve paid for a product that they think will protect them from being infected or getting sick.”

Many stem cell clinics have a history of selling unproven and unlicensed interventions for injuries and illnesses ranging from Alzheimer’s disease to pulmonary disorders to spinal cord injuries. Since the COVID-19 pandemic began, some have added claims about “immune-boosting” therapies for treating COVID-19 and acute respiratory distress syndrome (ARDS) caused by infection with SARS CoV-2. These companies advertise stem cell interventions and exosome products derived from such sources as umbilical cords and amniotic fluid. Turner says uncritical news media accounts have compounded some of these claims by reporting on preliminary evidence and case studies.

Yet rigorous clinical trials on these stem cell products have not yet been done. “Randomized controlled trials are needed to establish whether particular stem cell products are safe and efficacious in the treatment of COVID-19-related ARDS,” he explains.

Turner has studied the US direct-to-consumer marketplace for stem cell clinics for nearly a decade. “These businesses have a long history of claiming to treat diseases and injuries for which evidence-based therapies do not yet exist,” he says. To find out what these businesses were promoting, he did Google searches on a variety of terms related to stem cell treatments, COVID-19, and ARDS. He also searched YouTube for promotional videos made by these clinics.

“I found more examples of businesses peddling stem cell products for COVID-19 than I had space to describe in detail,” he notes. “I wasn’t surprised at how quickly some of these companies began making these claims. For them, the COVID-19 pandemic is an opportunity to generate a new revenue stream.”

In the paper, Turner also discusses the role of medical organizations, noting that while most are doing a good job of criticizing deceptive advertising, some have been promoting these interventions despite the lack of scientific evidence supporting their use.

“I want members of the public to know that some companies are trying to take advantage of them by selling supposed treatments that aren’t backed by credible evidence,” Turner concludes. “I’m also hoping that this paper will catch the attention of regulatory bodies like the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC), as well as state medical boards and state attorney general offices. The FDA and FTC have issued letters to some businesses, but additional regulatory action is needed.”

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Cell Stem Cell, Turner, L.: “Preying on Public Fears and Anxieties in a Pandemic: Businesses Selling Unproven and Unlicensed ‘Stem Cell Treatments’ for COVID-19” https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30201-0