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Researchers demonstrate how changing the stem cell response to inflammation may reverse periodontal disease — ScienceDaily

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Periodontal disease, also known as gum disease, is a serious infection that affects nearly 50 percent of Americans aged 30 years and older. If left unchecked, periodontal disease can destroy the jawbone and lead to tooth loss. The disease is also associated with higher risk of diabetes and cardiovascular disease.

The current treatment for periodontal disease involves opening the infected gum flaps and adding bone grafts to strengthen the teeth. But in new research published recently in the journal Frontiers in Immunology, Forsyth Institute scientists have discovered that a specific type of molecule may stimulate stem cells to regenerate, reversing the inflammation caused by periodontal disease. This finding could lead to the development of new therapeutics to treat a variety of systemic diseases that are characterized by inflammation in the body.

For the study, Dr. Alpdogan Kantarci, his PhD student Dr. Emmanuel Albuquerque, and their team removed stem cells from previously extracted wisdom teeth and placed the stem cells onto petri dishes. The researchers then created a simulated inflammatory periodontal disease environment in the petri dishes. Next, they added two specific types of synthetic molecules called Maresin-1 and Resolvin-E1, both specialized pro-resolving lipid mediators from omega-3 fatty acids. The scientists found that Mar1 and RvE1 stimulated the stem cells to regenerate even under the inflammatory conditions.

“Both Maresin-1 and Resolvin-1 reprogrammed the cellular phenotype of the human stem cells, showing that even in response to inflammation, it is possible to boost capacity of the stem cells so they can become regenerative,” said Dr. Kantarci, Associate Member of Staff at the Forsyth Institute.

This finding is important because it allows scientists to identify the specific protein pathways involved in inflammation. Those same protein pathways are consistent across many systemic diseases, including periodontal disease, diabetes, heart disease, dementia, and obesity.

“Now that we understand how these molecules stimulate the differentiation of stem cells in different tissues and reverse inflammation at a critical point in time, the mechanism we identified could one day be used for building complex organs” said Dr. Kantarci. “There is exciting potential for reprogramming stem cells to focus on building tissues.”

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Survey finds American support for human-animal chimera research — ScienceDaily

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In September 2015, the US National Institutes of Health placed a funding moratorium on research that involves introducing human pluripotent stem cells into animal embryos — a practice that experts say is vital for advancing the field of regenerative medicine. To assess attitudes on human-animal chimeric embryo research, investigators conducted a survey among 430 Americans. The results of the survey, which found that 82% of people are supportive of at least some parts of this research, appear October 1 in the journal Stem Cell Reports.

“The take-home point is that the overall support for this kind of research across the American public is strong,” says co-author Francis Shen, a professor of law at the University of Minnesota and executive director of the Harvard Massachusetts General Hospital Center for Law, Brain, and Behavior. “I think this speaks to the public’s interest in the transformative potential of regenerative medicine for addressing disease in a variety of organs.”

“Public attitudes were more supportive than I thought would have been possible in the current political climate,” says first author Andrew Crane, a researcher in the Department of Neurosurgery at the University of Minnesota.

Crane and senior author Walter Low, a professor in the Department of Neurosurgery and Stem Cell Institute at the University of Minnesota, conduct research on stem cell applications for neurological disorders like Parkinson’s disease. One project focuses on generating human neural stem cells within pig brains. After learning that colleagues in Japan had done a survey on public attitudes about this type of research, they decided to conduct a similar study in the United States. Low and Crane began a collaboration with the Japan group and with Shen, who specializes in ethics at the intersection of law and neuroscience.

The study included two waves of data collection: 227 participants were surveyed in July 2018 and 203 additional participants were surveyed in June 2020. The participants were recruited through an Amazon service called Mechanical Turk and were paid $1 for completing the survey. The questions in the survey were similar to those included in the Japanese study.

The participants knew “next to nothing “about this research going into the survey, Shen explains. “We used images, and we clarified how this research might be done, breaking it down into steps.”

The survey questions were designed to assess opinions on the progressive steps of human-animal chimeric embryo research, by asking participants which aspects of research they were willing to accept based on their personal feelings. For example, it included scenarios about first injecting human stem cells into a pig embryo, then transplanting that embryo into a pig uterus to produce a pig with a human organ, and finally transplanting that organ into a human patient. It also broke down research by organ, with support for some tissue types being higher than others: 61% for heart, 64% for blood, 73% for liver, and 62% for skin, versus 44% for sperm/eggs and 51% for brain.

“With regard to putting human brain cells into animal brains, we’ve heard concerns about the animals having some sort of human consciousness, but that’s quite far off from where the science is right now and from anything that we’ve tried to advocate for in our research,” Crane says. “We understand this is a concern that should not be taken lightly, but it shouldn’t prohibit us from moving the research forward.”

The survey was also designed to assess cultural differences, and the researchers were surprised to find that support was relatively high even among religious and cultural conservatives. The largest factor influencing opposition to the research was concern about animal rights.

“As investigators in the US, we’ve hit a roadblock with a lot of this research with regard to funding,” Crane says. He adds that a lack of funding could lead to the research moving to countries with fewer ethical safeguards in place.

“The three biggest concerns about this research are animal welfare, human dignity, and the possibility of neurological humanization,” Shen concludes. “We would love to do focus groups to look deeper at some of these questions.”

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Breakthrough for tomorrow’s dentistry — ScienceDaily

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New knowledge on the cellular makeup and growth of teeth can expedite developments in regenerative dentistry — a biological therapy for damaged teeth — as well as the treatment of tooth sensitivity. The study, which was conducted by researchers at Karolinska Institutet, is published in Nature Communications.

Teeth develop through a complex process in which soft tissue, with connective tissue, nerves and blood vessels, are bonded with three different types of hard tissue into a functional body part. As an explanatory model for this process, scientists often use the mouse incisor, which grows continuously and is renewed throughout the animal’s life.

Despite the fact that the mouse incisor has often been studied in a developmental context, many fundamental questions about the various tooth cells, stem cells and their differentiation and cellular dynamics remain to be answered.

Using a single-cell RNA sequencing method and genetic tracing, researchers at Karolinska Institutet, the Medical University of Vienna in Austria and Harvard University in the USA have now identified and characterised all cell populations in mouse teeth and in the young growing and adult human teeth.

“From stem cells to the completely differentiated adult cells we were able to decipher the differentiation pathways of odontoblasts, which give rise to dentine — the hard tissue closest to the pulp — and ameloblasts, which give rise to the enamel,” say the study’s last author Igor Adameyko at the Department of Physiology and Pharmacology, Karolinska Institutet, and co-author Kaj Fried at the Department of Neuroscience, Karolinska Institutet. “We also discovered new cell types and cell layers in teeth that can have a part to play in tooth sensitivity.”

Some of the finds can also explain certain complicated aspects of the immune system in teeth, and others shed new light on the formation of tooth enamel, the hardest tissue in our bodies.

“We hope and believe that our work can form the basis of new approaches to tomorrow’s dentistry. Specifically, it can expedite the fast expanding field of regenerative dentistry, a biological therapy for replacing damaged or lost tissue.”

The results have been made publicly accessible in the form of searchable interactive user-friendly atlases of mouse and human teeth. The researchers believe that they should prove a useful resource not only for dental biologists but also for researchers interested in development and regenerative biology in general.

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Fine-tuning stem cell metabolism prevents hair loss — ScienceDaily

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A team of researchers from Cologne and Helsinki has discovered a mechanism that prevents hair loss: hair follicle stem cells, essential for hair to regrow, can prolong their life by switching their metabolic state in response to low oxygen concentration in the tissue. The team was led by Associate Professor Sara Wickström (University of Helsinki and Max Planck Institute for the Biology of Ageing) and the dermatologist Professor Sabine Eming (University of Cologne), and included researchers from the University of Cologne’s Cluster of Excellence in Aging Research CECAD, the Max Planck Institute for the Biology of Ageing, Collaborative Research Centre 829 ‘Molecular Mechanisms Regulating Skin Homeostasis’, the Center for Molecular Medicine (CMMC) (all in Cologne), and the University of Helsinki. The paper ‘Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle’ has been published in Cell Metabolism.

Every day, tissues such as the skin and its hair follicles are exposed to environmental damage like ultraviolet radiation. Damaged material is continuously removed and renewed. On average, 500 million cells and 100 hairs are shed every day, amounting to 1.5 gram of material. The dead material is replaced by stem cells, which are specialized, highly proliferative and long-lived. Tissue function relies on the activity and health of these stem cells; compromised function or reduced number leads to aging. ‘Although the critical role of stem cells in aging is established, little is known about the mechanisms that regulate the long-term maintenance of these important cells. The hair follicle with its well understood functions and clearly identifiable stem cells was a perfect model system to study this important question’, said Sara Wickström.

To understand what made stem cells functionally distinct from their differentiated daughter cells, the team investigated the transcriptional and metabolic profiles of the two cell populations. ‘Intriguingly, these studies showed that stem cells and daughter cells have distinct metabolic characteristics’, said Dr. Christine Kim, co-leading scientist of the study. ‘Our analyses further predicted that Rictor, an important but relatively poorly understood molecular component of the metabolic master regulator mTOR pathway, would be involved.’ The mTOR signal transduction regulates processes like growth, energy, and oxygen consumption of cells.

In more detailed analyses, the team showed that stem cell depletion was due to the loss of metabolic flexibility. At the end of each regenerative cycle, during which a new hair is made, the stem cells will return to their specific location and resume a quiescent state. Dr. Xiaolei Ding, the other co-leading scientist, explained: ‘The key finding of this study is that this so called “fate reversibility” requires a shift from glutamine metabolism and cellular respiration to glycolysis. The stem cells reside in an environment with low oxygen availability and thus use glucose rather than glutamine as a carbon source for energy and protein synthesis. This shift is triggered by the low oxygen concentration and Rictor signaling. The removal of Rictor impaired the ability of this stem cell fate reversal, triggering slow, age-dependent exhaustion of the stem cells and age-induced hair loss.’ Ding and Eming had recently generated a genetic mouse model to study Rictor function and observed that mice lacking Rictor had significantly delayed hair follicle regeneration and cycling, which indicated impaired stem cell regulation. ‘Interestingly, with aging these mice showed hair loss and reduction in stem cell numbers’, said Ding.

‘A major future goal will be to understand how these preclinical findings might translate into stem cell biology in humans and potentially could be pharmaceutically harnessed to protect from hair follicle aging’, said Eming. ‘We are particularly excited about the observation that the application of a glutaminase inhibitor was able to restore stem cell function in the Rictor-deficient mice, proving the principle that modifying metabolic pathways could be a powerful way to boost the regenerative capacity of our tissues.’

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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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