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Stem cells can repair Parkinson’s-damaged circuits in mouse brains — ScienceDaily

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The mature brain is infamously bad at repairing itself following damage like that caused by trauma or strokes, or from degenerative diseases like Parkinson’s. Stem cells, which are endlessly adaptable, have offered the promise of better neural repair. But the brain’s precisely tuned complexity has stymied the development of clinical treatments.

In a new study addressing these hurdles, University of Wisconsin-Madison researchers demonstrated a proof-of-concept stem cell treatment in a mouse model of Parkinson’s disease. They found that neurons derived from stem cells can integrate well into the correct regions of the brain, connect with native neurons and restore motor functions.

The key is identity. By carefully tracking the fate of transplanted stem cells, the scientists found that the cells’ identity — dopamine-producing cells in the case of Parkinson’s — defined the connections they made and how they functioned.

Coupled with an increasing array of methods to produce dozens of unique neurons from stem cells, the scientists say this work suggests neural stem cell therapy is a realistic goal. However, much more research is needed to translate findings from mice to people.

The team, led by UW-Madison neuroscientist Su-Chun Zhang, published its findings Sept. 22 in the journal Cell Stem Cell. The research was led by Zhang lab postdoctoral researchers Yuejun Chen, Man Xiong and Yezheng Tao, who now hold faculty positions in China and Singapore.

“Our brain is wired in such an accurate way by very specialized nerve cells in particular locations so we can engage in all our complex behaviors. This all depends on circuits that are wired by specific cell types,” says Zhang, a professor of neuroscience and neurology at UW-Madison’s Waisman Center. “Neurological injuries usually affect specific brain regions or specific cell types, disrupting circuits. In order to treat those diseases, we have to restore these circuits.”

To repair those circuits in the Parkinson’s disease mouse model, the researchers began by coaxing human embryonic stem cells to differentiate into dopamine-producing neurons, the kind of cells that die in Parkinson’s. They transplanted these new neurons into the midbrains of mice, the brain region most affected by Parkinson’s degeneration.

Several months later, after the new neurons had time to integrate into the brain, the mice showed improved motor skills. Looking closely, Zhang’s group was able to see that the transplanted neurons grew long distances to connect to motor-control regions of the brain. The nerve cells also established connections with regulatory regions of the brain that fed into the new neurons and prevented them from being overstimulated.

Both sets of connections — feeding in and out of the transplanted neurons — resembled the circuitry established by native neurons. This was only true for dopamine-producing cells. Similar experiments with cells producing the neurotransmitter glutamate, which is not involved in Parkinson’s disease, did not repair motor circuits, revealing the importance of neuron identity in repairing damage.

To finally confirm that the transplanted neurons had repaired the Parkinson’s-damaged circuits, the researchers inserted genetic on-and-off switches into the stem cells. These switches turn the cells’ activity up or down when they are exposed to specialized designer drugs in the diet or through an injection.

When the stem cells were shut down, the mice’s motor improvements vanished, suggesting the stem cells were essential for restoring Parkinson’s-damaged brains. It also showed that this genetic switch technology could be used to fine-tune the activity of transplanted cells to optimize treatment.

The Zhang group and other researchers have spent years developing methods to turn stem cells into the many different types of neurons within the brain. Each neurological disease or injury would require its own specialized nerve cells to treat, but the treatment plans would likely be broadly similar. “We used Parkinson’s as a model, but the principle is the same for many different neurological disorders,” says Zhang.

The work has personal meaning to Zhang. As a physician and scientist, he often receives letters from families desperate for help treating neurological disorders or brain trauma. It’s also an experience he can relate to. Six years ago, Zhang was in a bike accident and broke his neck. When he awoke partially paralyzed in the hospital, his first thought was of how stem cells — which he had already researched for years — could help him recover.

Now, largely rehabilitated after years of physical therapy, Zhang still believes that the right stem cell treatments could, in the future, help people like him and the families he hears from.

To that end, Zhang’s group is currently testing similar treatments in primates, a step toward human trials.

“There is hope, but we need to take things one step at a time,” he says.

This work was supported in part by the National Institutes of Health (grants NS096282, NS076352, and NS086604, MH099587 and MH100031).

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Placenta is initiated first, as cells of a fertilized egg divide and specialize — ScienceDaily

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The first stages of placental development take place days before the embryo starts to form in human pregnancies. The finding highlights the importance of healthy placental development in pregnancy, and could lead to future improvements in fertility treatments such as IVF, and a better understanding of placental-related diseases in pregnancy.

In a study published in the journal Nature, researchers looked at the biological pathways active in human embryos during their first few days of development to understand how cells acquire different fates and functions within the early embryo.

They observed that shortly after fertilisation as cells start to divide, some cells start to stick together. This triggers a cascade of molecular events that initiate placental development. A subset of cells change shape, or ‘polarise’, and this drives the change into a placental progenitor cell — the precursor to a specialised placenta cell — that can be distinguished by differences in genes and proteins from other cells in the embryo.

“This study highlights the critical importance of the placenta for healthy human development,” said Dr Kathy Niakan, group leader of the Human Embryo and Stem Cell Laboratory at the Francis Crick Institute and Professor of Reproductive Physiology at the University of Cambridge, and senior author of the study.

Niakan added: “If the molecular mechanism we discovered for this first cell decision in humans is not appropriately established, this will have significant negative consequences for the development of the embryo and its ability to successfully implant in the womb.”

The team also examined the same developmental pathways in mouse and cow embryos. They found that while the mechanisms of later stages of development differ between species, the placental progenitor is still the first cell to differentiate.

“We’ve shown that one of the earliest cell decisions during development is widespread in mammals, and this will help form the basis of future developmental research. Next we must further interrogate these pathways to identify biomarkers and facilitate healthy placental development in people, and also cows or other domestic animals,” said Claudia Gerri, lead author of the study and postdoctoral training fellow in the Human Embryo and Stem Cell Laboratory at the Francis Crick Institute.

During IVF, one of the most significant predictors of an embryo implanting in the womb is the appearance of placental progenitor cells under the microscope. If researchers could identify better markers of placental health or find ways to improve it, this could make a difference for people struggling to conceive.

“Understanding the process of early human development in the womb could provide us with insights that may lead to improvements in IVF success rates in the future. It could also allow us to understand early placental dysfunctions that can pose a risk to human health later in pregnancy,” said Niakan.

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New way to halt leukemia relapse shown promising in mice — ScienceDaily

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Researchers have identified a second path to defeating chronic myelogenous leukemia, which tends to affect older adults, even in the face of resistance to existing drugs.

The new findings were published on September 17th in Nature Communications.

Almost all patients with chronic myelogenous leukemia, or CML, have a faulty, cancer-causing gene, or “oncogene” called BCR-ABL1. BCR-ABL1 turns a regular stem cell (a unique type of cell that can turn into other types of cells and then reproduce those cells during life time) in the bone marrow into a CML stem cell that produces malformed blood cells. And instead of the CML stem cell dying when it should be scheduled to do so, the oncogene causes it to keep producing even more of these faulty blood cells.

Advances in treatment since the turn of the millennium have been extremely successful at combatting the disease in patients with this oncogene. Drugs called tyrosine kinase inhibitors (TKI) have completely transformed the prognosis of people with such leukemias, and with fewer of the side effects of other cancer treatments. In most cases, the cancer goes into remission and patients live for many years following diagnosis.

BCR-ABL1 directs the production of an abnormal type of tyrosine kinase, an enzyme that ‘turns on’ many types of proteins through a cascade of chemical reactions known as signal transduction — in effect communication via chemistry. Miscommunication resulting from the faulty enzyme is what promotes the growth of the leukemic cells. By stopping this communication within CML stem cells, TKI signal transduction therapy inhibits their growth and brings a halt to their production of the malformed blood cells.

However, TKIs only controls the disease; they don’t cure it. Drug resistance can develop in a patient because while TKIs work well on proliferative mature CML cells that are actively reproducing, they are less effective at inducing cell death on the part of CML stem cells that are quiescent.

Quiescence is an “idling” stage in the life cycle of a cell in which it basically just rests and hangs out for extended periods of time in anticipation of reactivation, neither replicating nor dying.

“If CML stem cells are in a quiescent phase, they are otherwise left untouched by TKI treatment, and so survive to potentially cause a relapse,” said Kazuhito Naka, paper author and an associate professor from the Department of Stem Cell Biology of Hiroshima University’s Research Institute for Radiation Biology and Medicine.

But the researchers found in mouse models that if they disrupt Gdpd3 — a different, non-oncogene gene — then the self-renewal capacity of the CML stem cells is sharply decreased. Gdpd3 directs the production of an enzyme for a particular type of lipid that appears to play a key role in regulating the quiescence of CML stem cells in an oncogene-independent fashion.

In other words, the Gdpd3 gene involved in production of this lipid is largely responsible for the maintenance of CML stem cells. The researchers had broken their quiescence.

Crucially, when the researchers disrupted the Gdpd3 gene encoding these lipids, leukemia relapse in the mice was significantly reduced, even when the BCR-ABL1 oncogene was not disrupted.

“This potentially provides another path to arresting these leukemias — and maybe other cancers too,” said Dr. Naka, “beyond having to wrestle with the BCR-ABL1 oncogene.”

While the researchers have discovered a new, biologically significant role for this particular lipid in causing the recurrence of CML, they still do not fully understand the precise way this happens. The researchers now want to investigate the mechanisms involved and whether this lipid also plays a role in the quiescence of the cancer stem cells that cause solid tumors, not just in leukemias, and thus in these cancers’ recurrence and growth as well.

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Uncovering the clock that sets the speed of embryo development — ScienceDaily

Why do pregnancies last longer in some species than others? Researchers at the Francis Crick Institute have found the clock that sets the speed of embryonic development and discovered the mechanism is based on how proteins are made and dismantled. The study, published in Science, could also help us understand how different mammals evolved from one another and help refine methods for regenerative medicine.

Different development time-scales

All mammals follow the same steps to grow from embryo to adult. This involves the same series of events, in the same sequence, using similar genes and molecular signals. However, the speed of progress through these steps differs considerably from one species to another. For instance, motor neurons — the nerve cells that control muscle movement — take about three days to develop in mice, but over a week to develop in humans.

To understand what governs this speed in different species, researcher Teresa Rayon and colleagues in James Briscoe’s Developmental Dynamics lab at the Crick first grew motor neurons from stem cells in the lab, so they could time the cells’ development without any influence from the environment within the embryo.

Using mouse and human stem cells, they saw the same difference in speed between the species. Human motor neurons took more than twice as long as mouse motor neurons to form, so they knew the answer must lie within the cells themselves, not the surrounding environment.

They also checked if the genes were responsible, by introducing human DNA sequences into mouse cells. However, this did not alter the speed of development, so the answer wasn’t in the genes either.

Finding an answer in the proteins

Instead, the researchers discovered that differences in the speed at which proteins are broken down and replaced explains the difference in speed between the two species. Proteins are constantly turned over — made and dismantled — in cells, and this happens twice as fast in mouse cells compared to human cells. This faster rate of protein turnover in mouse cells accounts for the faster pace of motor neuron formation.

Teresa Rayon explained, “Human and mouse motor neurons use the same genes and molecules for their embryonic development, it just takes longer for the process to play out in humans. Proteins are simply more stable in humans than mouse embryos and this slows the rate of human development.”

“It’s as if mouse and human embryos are reading the same musical score and playing the same tune but the metronome ticks more slowly in humans than in mice. Now that we’ve found the metronome, we want to understand how to change its speed.”

How this impacts research and treatments

Understanding the mechanisms that control the speed of development has implications for regenerative medicine and for the use of stem cells in understanding disease. Being able to speed up or slow down the development of stem cells could help refine methods for the production of specific types of cells for research and therapeutic applications and it might also provide insight relevant for slowing the growth of cells in diseases such as cancer.

James Briscoe, who led the team of researchers said, “Changes in developmental time, so called heterochronies, play a profound role in the evolution of differences in body shapes and sizes between species. For example, the human brain is larger because its cells grow for a longer period of time during embryonic development than the equivalent cells in mice. So beyond practical applications, understanding how the tempo of embryonic development is controlled has the potential to help us understand how different species evolved.”

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Generation of three-dimensional heart organoids — ScienceDaily

Researchers from Tokyo Medical and Dental University (TMDU) use mouse embryonic stem cells to engineer three-dimensional functional heart organoids resembling the developing heart

Heart development as it happens in vivo, or in a living organism, is a complex process that has traditionally been difficult to mimic in vitro, or in the laboratory. In a new study, researchers from Tokyo Medical and Dental University (TMDU) developed three-dimensional functional heart organoids from mouse embryonic stem cells that closely resemble the developing heart.

The heart consists of multiple layers of tissue including many different cell types, including working heart muscle, connective tissue cells, and cells that make up blood vessels. These cells work together to ensure a proper functioning of the heart and thus the constant supply of fresh, oxygenated blood to the rest of the body. Studying all forms of heart disease in the laboratory and developing novel drugs to treat these diseases require disease models that closely resemble the actual heart. While effort has been made to generate heart muscle cells in vitro, these cells present as clumps without the tissue organization seen in vivo.

“Despite its seemingly simple function, the heart is a complex organ with an even more complex structure,” say corresponding authors of the study Professors Jiyoung Lee and Fumitoshi Ishino. “To achieve that level of structural complexity, during development the heart is exposed to a myriad of signals. We wanted to capitalize on our knowledge of the signaling molecules during heart development and generate heart organoids that resemble the developing heart more closely than current techniques.”

To achieve their goal, the researchers looked into the factors involved in heart development in vivo and speculated that the protein fibroblast growth factor 4 (FGF4) and a complex consisting of the proteins laminin and entactin (LN/ET complex), all of which are known are expressed in the embryonic heart, are necessary and sufficient to enable structural similarity between the heart organoids and the actual embryonic heart. Indeed, mouse embryonic stem cells exposed to FGF4 and LN/ET showed considerable similarity to the developing heart based on structural as well as molecular analyses.

Intriguingly, the process of development in the heart organoids closely reflected the morphological changes during embryonic heart development in vivo. A closer look at the cellular components making up the heart organoids revealed that cells of the embryonic heart, including cells of all four chambers as well as of the conduction system, were present in the structural organization seen during embryonic development. Importantly, the heart organoids possessed functional properties close to their in vivo-counterpart.

“These are striking results that show how our method provides a biomimetic model of the developing heart using a rather simple protocol. This tool could be helpful in studying the molecular processes during heart development, and in developing and testing novel drugs against heart disease,” say Professors Lee and Ishino.

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Next-gen organoids grow and function like real tissues — ScienceDaily

Organoids are fast-becoming one of the most cutting-edge tools of modern life sciences. The idea is to use stem cells to build miniature tissues and organs that accurately resemble and behave like their real counterparts.

One can immediately appreciate the value of organoids for both research and medicine: from basic biological research to drug development and testing, organoids could complement animal testing by providing healthy or diseased human tissues, expediting the lengthy journey from lab to clinical trial. Beyond that, there is already the whisper of organoid technology perhaps being used for replacing damaged tissues or even organs in the future: take stems cells from the patient and grow them into a new liver, heart, kidney, or lung.

So far, established methods of making organoids come with considerable drawbacks: stem cells develop uncontrollably into circular and closed tissues that have a short lifespan, as well as non-physiological size and shape, all of which result in overall anatomical and/or physiological inconsistency with real-life organs.

Now, scientists from the group led by Matthias Lütolf at EPFL’s Institute of Bioengineering have found a way to “guide” stem cells to form an intestinal organoid that looks and functions just like a real tissue. Published in Nature, the method exploits the ability of stem cells to grow and organize themselves along a tube-shaped scaffold that mimics the surface of the native tissue, placed inside a microfluidic chip (a chip with little channels in which small amounts of fluids can be precisely manipulated).

The EPFL researchers used a laser to sculpt this gut-shaped scaffold within a hydrogel, a soft mix of crosslinked proteins found in the gut’s extracellular matrix supporting the cells in the native tissue. Aside from being the substrate on which the stem cells could grow, the hydrogel thus also provides the form or “geometry” that would build the final intestinal tissue.

Once seeded in the gut-like scaffold, within hours, the stem cells spread across the scaffold, forming a continuous layer of cells with its characteristic crypt structures and villus-like domains. Then came the surprise: the scientists found that, the stem cells just “knew” how to arrange themselves in order to form a functional tiny gut.

“It looks like the geometry of the hydrogel scaffold, with its crypt-shaped cavities, directly influences the behavior of the stem cells so that they are maintained in the cavities and differentiate in the areas outside, just like in the native tissue,” says Lütolf. The stem cells didn’t just adopt to the shape of the scaffold, they produced all the key differentiated cell types found in the real gut, with some rare and specialized cell types normally not found in organoids.

Intestinal tissues are known for the highest cell turnover rates in the body, resulting in a massive amount of shed dead cells accumulating in the lumen of the classical organoids that grow as closed spheres and require weekly breaking down into small fragments to maintain them in culture. “The introduction of a microfluidic system allowed us to efficiently perfuse these mini-guts and establish a long-lived homeostatic organoid system in which cell birth and death are balanced,” says Mike Nikolaev, the first author of the paper.

The researchers demonstrate that these miniature intestines share many functional features with their in vivo counterparts. For example, they can regenerate after massive tissue damage and they can be used to model inflammatory processes or host-microbe interactions in a way not previously possible with any other tissue model grown in the laboratory.

In addition, this approach is broadly applicable for the growth of miniature tissues from stem cells derived from other organs such as the lung, liver or pancreas, and from biopsies of human patients. “Our work shows that tissue engineering can be used to control organoid development and build next-gen organoids with high physiological relevance, opening up exciting perspectives for disease modelling, drug discovery, diagnostics and regenerative medicine,” says Lütolf.

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Materials provided by Ecole Polytechnique Fédérale de Lausanne. Original written by Nik Papageorgiou. Note: Content may be edited for style and length.

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A new discovery in regenerative medicine — ScienceDaily

An international collaboration involving Monash University and Duke-NUS researchers have made an unexpected world-first stem cell discovery that may lead to new treatments for placenta complications during pregnancy.

While it is widely known that adult skin cells can be reprogrammed into cells similar to human embryonic stem cells that can then be used to develop tissue from human organs — known as induced pluripotent stem cells (iPSCs) — the same process could not create placenta tissue.

iPSCs opened up the potential for personalised cell therapies and new opportunities for regenerative medicine, safe drug testing and toxicity assessments, however little was known about exactly how they were made.

An international team led by ARC Future Fellow Professor Jose Polo from Monash University’s Biomedicine Discovery Institute and the Australian Research Medicine Institute, together with Assistant Professor Owen Rackham from Duke-NUS in Singapore, examined the molecular changes the adult skin cells went through to become iPSCs. It was during the study of this process that they discovered a new way to create induced trophoblast stem cells (iTSCs) that can be used to make placenta cells.

This exciting discovery, also involving the expertise of three first authors, Dr. Xiaodong Liu, Dr. John Ouyang and Dr. Fernando Rossello, will enable further research into new treatments for placenta complications and the measurement of drug toxicity to placenta cells, which has implications during pregnancy.

“This is really important because iPSCs cannot give rise to placenta, thus all the advances in disease modelling and cell therapy that iPSCs have brought about did not translate to the placenta,” Professor Polo said.

“When I started my PhD five years ago our goal was to understand the nuts and bolts of how iPSCs are made, however along the way we also discovered how to make iTSCs,” said Dr Liu.

“This discovery will provide the capacity to model human placenta in vitro and enable a pathway to future cell therapies,” commented Dr Ouyang.

“This study demonstrates how by successfully combining both cutting edge experimental and computational tools, basic science leads to unexpected discoveries that can be transformative,” Professor Rackham said.

Professors Polo and Rackham said many other groups from Australian and international universities contributed to the study over the years, making it a truly international endeavour.

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Scientists are learning about species adaptation by comparing their stem cell-related genes — ScienceDaily

The genes regulating pluripotent stem cells in mammals are surprisingly similar across 48 species, Kyoto University researchers report in the journal Genome Biology and Evolution. The study also shows that differences among these ‘gene regulating networks’ might explain how certain features of mammalian pluripotent stem cells have evolved.

Pluripotent stem cells can self-renew and give rise to all other types of cells in the body. Their characteristics are controlled by a network of regulatory genes and molecules, but little is known about how this network has evolved across mammals.

To this end, Ken-ichiro Kamei of Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS), with Miho Murayama and Yoshinori Endo of the Wildlife Research Center, compared 134 gene sets belonging to the pluripotency gene regulatory networks of 48 mammalian species.

They found that this network has been highly conserved across species, meaning genetic sequences have remained relatively unchanged over the course of evolution. This high degree of conservation explains why human genetic sequences can reprogram other mammalian tissue cells to turn into pluripotent stem cells. However, since it is also evident that the regulating networks differ across mammals, there might be more efficient combinations of reprogramming factors for each species. Improving techniques for deriving induced pluripotent stem (iPS) cells from mammalian cells, including those from endangered species, could provide a big boost to research and conservation.

“We have been trying to generate induced pluripotent stem cells from various mammalian species, such as the endangered Grévy’s zebra and the bottlenose dolphin,” says Kamei.

Interestingly, the team found relatively high evolutionary changes in genes just downstream of one of the core gene regulatory networks. “This could indicate that mammalian pluripotent stem cells have diversified more than we thought,” says Inoue-Murayama.

The differences between gene regulatory networks in mammalian pluripotent stem cells might also be associated with unique adaptions.

For example, the naked mole rat has been positively selected for a pluripotency regulatory gene that could be involved in giving it its extraordinary longevity and cancer resistance. The gene might also be involved in the development of the extremely sensitive hairs that help them navigate underground.

The researchers also found evidence of positive selection for certain pluripotency gene regulatory network genes involved in the adaptation of large animals, such as the minke whale, the African elephant and the flying fox, to their environments. Surprisingly, these same genes are associated with cancer in other mammals. Since these large animals are known for being relatively resistant to cancer, the researchers suggest that the adaptive alterations these genes underwent in these animals somehow also changed some of their functions, thus giving this group a degree of cancer resistance.

The researchers say the study is among the first to compare the pluripotency gene regulatory networks across major taxa, and could be applicable to evolutional biology studies and for facilitating and improving the generation of induced pluripotent stem cells from new species.

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Gene that drives ovarian cancer identified — ScienceDaily

High-grade serious ovarian carcinoma (HGSOC) is the fifth-leading cause of cancer-related deaths in women in the United States, yet little is known about the origins of this disease.

Now, scientists at the College of Veterinary Medicine have collaborated on a study that pinpoints which specific genes drive — or delay — this deadly cancer.

“We’ve taken the enormous collection of genomic mutation data that’s been mined on cancer genetics and tried to make functional sense of it,” said John Schimenti, professor of genetics in the Department of Biomedical Sciences and senior author of the study, which published Sept. 1 in Cell Reports.

Schimenti teamed with biomedical sciences colleague Alexander Nikitin, professor of pathology and director of the Cornell Stem Cell Program, and members of their respective labs to gain a better understanding of HGSOC.

Cancer researchers have known for a while that the disease is almost always caused by multiple genetic “hits.” One mutation alone does not turn a cell cancerous; generally at least two or three are required, and often different combinations of genes can cause the same cancer.

Adding complexity, Schimenti said, is the fact that once one key genome-destabilizing mutation arises, others will follow. Sequenced tumors yield a plethora of mutations — some are the originators of the cancer itself, while many others are spinoffs.

“It’s a longstanding issue in cancer research,” he said. “What are the genetic drivers, and what are the passengers in the process?”

To address these complexities, the researchers wanted to test combinations of possible genetic suspects, and then parse out which of the many associated mutations were sparking the cancer.

To do so, they turned to the Cancer Genome Atlas, an international collaborative database that compiles the genetic information from patient tumor samples and the mutated genes associated with them. They took a list of 20 genes known to mutate in HGSOC and, using CRISPR gene-editing technology, created random combinations of these mutations in cultured cells from the ovary surface, including regular epithelial cells and epithelial stem cells, to see which cell type was more susceptible to the mutations.

The researchers then noted which combination of mutations turned which group of cells cancerous — pinpointing both the genes driving the process and which cell type the cancer originated in.

The study revealed what the team had originally suspected — that ovarian surface stem cells were more apt to become cancerous when hit with mutations. They also unexpectedly discovered genes that had the opposite effect.

“We found there were various genes that would help the process along, but interestingly, there were other genes that, when mutated, actually inhibited the cancer initiation process,” Schimenti said.

Knowing which are the cells of origin and which genes are necessary in initiating this highly aggressive form of ovarian cancer can be powerful information, both for ovarian and other types of cancers. “The cancer driver screening methodology we used should be applicable to answering the same kinds of questions for cells and cancers in other organs and tissues,” Nikitin said.

Schimenti said the findings could be particularly useful for ovarian cancer patients who have their tumors biopsied and sequenced for genetic data.

“In the past, you would know which genes were mutated but you wouldn’t know what role they played,” he said. “Now you know which ones are important. And eventually, you could develop drugs to target the mutated genes that you know are causing the problem.”

This work was supported by grants from the Ovarian Cancer Research Fund, the New York State Stem Cell Science Program, the National Institutes of Health and the National Cancer Institute.

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Materials provided by Cornell University. Original written by Lauren Cahoon Roberts. Note: Content may be edited for style and length.

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Mini-organs could offer treatment hope for children with intestinal failure — ScienceDaily

Pioneering scientists at the Francis Crick Institute, Great Ormond Street Hospital (GOSH) and UCL Great Ormond Street Institute of Child Health (ICH) have grown human intestinal grafts using stem cells from patient tissue that could one day lead to personalised transplants for children with intestinal failure, according to a study published in Nature Medicine today (Monday 7th September).

Children with intestinal failure cannot absorb the nutrients that are essential for their overall health and development. This may be due to a disease or injury to their small intestine.

In these cases, children can be fed intravenously via a process called parenteral nutrition, however this is associated with severe complications such as line infections and liver failure. If complications arise or in severe cases these children may need a transplant. However, there is a shortage of suitable donor organs and problems can arise after surgery, such as the body rejecting the transplant.

In their proof-of-concept study, the research team showed how intestinal stem cells and small intestinal or colonic tissue taken from patients can be used to grow the important inner layer of small intestine in the laboratory with the capacity to digest and absorb peptides and digest sucrose in food.

This is the first step in efforts to engineer all the layers of the intestine for transplantation. The researchers hope that one day, laboratory grown organs could offer a safe and longer-lasting alternative to traditional donor transplants.

“It’s urgent that we find new ways to care for children without a working intestine because, as they grow older, complications from parental nutrition can arise,” says Dr Vivian Li, senior author and group leader of the Stem Cell and Cancer Biology Laboratory at the Crick.

“We’ve set out a process to grow one layer of intestine in the laboratory, moving us a step closer to being able to offer these patients a form of regenerative medicine, which uses materials created from their own tissue. This would reduce some of the risks that transplant patients face, such as their immune system attacking the transplant.”

The researchers took small biopsies of intestine from 12 children who either had intestinal failure or were at risk of developing the condition. In the lab, they then stimulated the biopsy cells to grow into “mini-guts,” also known as intestinal organoids, generating over 10 million intestinal stem cells from each patient over the course of 4 weeks.

The researchers also collected small intestine and colon tissue, that would otherwise have been discarded, from other children undergoing essential surgery to remove parts of their gut. Using laboratory techniques, cells were removed from these tissues leaving behind a skeleton structure which formed scaffolds.

The researchers placed the “mini-guts” onto these scaffolds, where they grew on this structure to form a living graft. Due to specific culture conditions, the stem cells changed into many of the different types of cells that exist in the small intestine. The grafts were able to digest and absorb peptides, the building blocks of proteins, as well as digest sucrose into glucose sugars.

“Although this research is in the lab right now, we’re concentrating on making this a realistic and safe treatment option,” explains senior author NIHR Professor Paolo De Coppi, Consultant Paediatric Surgeon at GOSH and Head of Surgery, Stem Cells & Regenerative Medicine Section at the UCL Great Ormond Street Institute of Child Health (ICH).

“What’s significant here is we’ve shown that scaffolds can be created using tissue from the colon, not only tissue from the small intestine. In practice, it is often easier to obtain tissue from the colon, so this could make the approach much more feasible. It’s an important step forward in regenerative medicine and we’re optimistic about what this means for patients, but more research lies ahead before we can safely and effectively translate this approach to treatment.”

As well as proving that biopsies taken from children could be used to grow functioning intestinal grafts, the researchers also demonstrated that the grafts survive and mature when transplanted into mice.

“By applying our basic science knowledge of intestinal stem cell biology, we have developed a time efficient and clinically relevant method for rebuilding human small intestine grafts for transplantation,” says Laween Meran, lead author, Gastroenterology Registrar and Clinical Research Training Fellow at the Stem Cell and Cancer Biology Laboratory at the Crick and the ICH.

“Now that we’ve shown the grafts are successful on a small scale, the next crucial steps will be to start growing the other layers of the intestine such as muscle and blood vessels, whilst also scaling up our methods to create viable grafts relevant to individual patient needs.”

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