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New subtype of muscle stem cells that can be used in the development of gene therapies — ScienceDaily

Anyone who climbs the 285 steps to the viewing platform of Berlin’s Siegessäule, or Victory Column, will probably have quite a few sore muscles the next day. Out-of-the-ordinary activities such as climbing lots of steps or even normal exercise can put significant strain on muscles. Such activities cause tiny tears in the muscle fibers, which the body then repairs on its own.

Even when injuries occur, the muscles activate an endogenous regeneration program: A reserve supply of muscle stem cells, known as satellite cells, reside around the muscle fibers and are essential for the repair of damaged muscle cells. These satellite cells produce new muscle fibers in a process which results in muscle regeneration. People maintain this ability well into old age. Researchers are particularly interested in these cells since they could provide targets for new therapeutic approaches for people with muscle diseases.

An overrated protein

Researchers previously assumed that a certain protein — the transcription factor PAX7 — plays a key role in muscle regeneration. “Cells from which new muscles arise have enormous potential for developing gene therapies to treat muscle atrophy. And PAX7 is actually considered a characteristic property of muscle-building satellite cells,” says Prof. Simone Spuler.

The scientist and physician is a research group leader at the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité — Universitätsmedizin Berlin, and heads the Myology Group at the MDC. Her team has now reported in the journal Nature Communications that it’s possible for muscles to grow and regenerate without PAX7. The study characterized a previously unknown subtype of satellite cells that could play an important role in the future development of gene therapies from muscle stem cells.

“The findings will certainly surprise many researchers in the field,” says Dr. Andreas Marg, a senior scientist in Spuler’s lab and the lead author of the study. He himself was initially guided by the assumption that the transcription factor was crucial for muscle growth. “I previously focused my research on PAX7-positive cells. Our findings lead us down a new path.”

New muscles despite a mutation

The research team owes the discovery to a young girl: Lavin has suffered from a genetic form of muscular dystrophy since birth and is the protagonist in the study. Lavin has all the muscles of a healthy person, but each of her muscles is very small. The musculature along her spine is particularly affected by the disease. Lavin’s arms and legs are strong, but she suffers breathing problems and has difficulty bending forward and holding her head up.

Gene analysis shows that the gene for PAX7 is damaged in Lavin; her cells can’t produce this protein. The University Hospital Munich discovered this in 2017. Soon thereafter, Spuler and Marg learned of this extremely rare mutation — one that had not been described before. Lavin traveled with her parents to the Berlin-Buch campus, where the scientists took a sample of her muscle tissue. Marg used a new procedure to filter out Lavin’s satellite cells and then implanted them in mice. He observed that new muscle fibers grew in the mice from Lavin’s cells — despite the absence of PAX7.

Spuler presumes that PAX7 is not equally important for every cell. This would explain why Lavin can walk and climb relatively well, but has hardly any strength in her diaphragm, which causes the breathing problems. “We could perhaps develop a gene therapy for Lavin using the CRISPR-Cas9 gene-editing tool,” says Spuler. “However, to repair the defective gene, CRISPR-Cas9 would have to specifically target the cells of the axial musculature, and that is not yet possible.” But Spuler’s lab is working intensively to figure out how to repair defective genes in muscle cells. For Lavin and her family, this research offers a small glimmer of hope that a suitable therapy will be found.

A new subtype of muscle stem cells

Marg and Spuler collaborated on the study with many colleagues at the MDC and with scientists from institutions abroad. Prof. Nikolaus Rajewsky’s research group at the Berlin Institute for Medical Systems Biology (BIMSB) compared Lavin’s cells with those donated by healthy people. Single-cell analysis, which looks at the activity of each cell individually, revealed a previously unknown cell population. In around 20 percent of the donors, the majority of the activated satellite cells also don’t produce any PAX7, even though the genetic information is present in the cells. The team instead discovered something else in those cells in which the transcription factor was missing: CLEC14A, a protein that is found in many blood vessel cells. This very protein was highly expressed in Lavin’s muscle stem cells.

The new study describes a previously unknown subtype of satellite cells. First, the researchers identified these cells in the stem cell niche, which is where the satellite cells reside. Second, PAX7 is not present in these cells. Third, other characteristic proteins such as CLEC14A are present instead. And fourth, new muscle fibers can be derived from this cell population.

Up to now, only cells with PAX7 have been considered as targets for gene therapy research involving satellite cells. The new study shows that the subtype discovered should also play a role in therapeutic development.

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Mouse pups born from eggs derived from the granulosa cells that surround oocytes — ScienceDaily

By introducing a chemical cocktail to granulosa cells, researchers in China induced the cells to transform into functional oocytes in mice. Once fertilized, these oocytes were then successfully able to produce healthy offspring, showing no differences from naturally bred mice. The chemical reprogramming method appears December 24 in the journal Cell Reports.

Ovarian follicles are the basic functional unit of the ovary and consist of an oocyte, the immature egg, which is surrounded by granulosa cells. Besides being crucial to the development of follicles, studies have shown that granulosa cells possess plasticity that shows stem cell-like properties.

“The thing about in vitro fertilization is that they only use the oocyte for the procedure,” says senior author Lin Liu, of the College of Life Sciences at Nankai University. “After the egg retrieval, the granulosa cells in the follicle are discarded. It got us thinking, what if we can utilize these granulosa cells? Since every egg has thousands of granulosa cells surrounding it, if we can induce them into pluripotent cells and turn those cells into oocytes, aren’t we killing two birds with one stone?”

Granulosa cells tend to undergo cell death and differentiation once removed from the follicles. Liu and his team including PhD students Chenglei Tian and Haifeng Fu developed a chemical “cocktail” with Rock inhibitor and crotonic acid for creating chemically induced pluripotent stem cells (CiPSCs) from granulosa cells. The research team introduced Rock inhibitor to prevent cell death and promote proliferation. In combination with other important small chemicals, crotonic acid facilitates the induction of granulosa cells into germline-competent pluripotent stem cells that exhibit pluripotency similar to embryonic stem cells.

“It’s a surprising result,” says Liu. “The competency of induced pluripotent germline is usually lower than embryonic stem cells. Germline competency is crucial for germline cells to transfer genetic information to the next generation. With the co-formulation of Rock inhibitor and crotonic acid, it’s not only more efficient, but the quality also increased.”

Another cocktail of Rock inhibitor and vitamin C is introduced to the germline-competent pluripotent stem cells to improve the follicle development and induce meiosis. Meiosis is the process of a single cell becoming sex cells, the egg. Germ cells and oocytes rejuvenated from granulosa cells exhibit high genomic stability and successfully produce offspring that show normal fertility.

“We can consistently manipulate the concentration and treatment time of these small chemicals,” says Liu. Compared to traditional stem cell-inducing methods such as transfection, which reprograms cells by introducing transcription factors to somatic cells, chemical treatment provides higher controllability. “Transfection method may have a higher risk of genetic instability.”

“This is the first time we turned granulosa cells into oocytes, it is a crucial and interesting work in developmental and reproductive biology,” he says. “But implementing this research to humans from mice still has a long way to go. I think it has more prospect in preserving fertility and endocrine function, than in treating infertility.”

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Materials provided by Cell Press. Note: Content may be edited for style and length.

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Modeling the human eye in a dish — ScienceDaily

Despite its small size relative to the rest of the body, the eye is one of the most complex organs of the human body and has been difficult to study in a lab. Now, researchers from Osaka University have developed a novel method to model eye development and disease using human induced pluripotent stem cells (hiPSCs). In a new study published in Journal of Biological Chemistry, they showed how tracking the expression of PITX2, a key protein during eye development, in developing hiPSCs enables the isolation of a certain group of cells that play important roles in eye development, biology and disease.

Ever since their discovery over a decade ago, hiPSCs have continued to be used to replicate human biology and disease in a lab without the need for animals. Their streamlined use is accompanied by the possibility of easily genetically altering the cells to study the function of proteins. Although to date several cellular models of multiple organs have been developed using hiPSC, due to its complex and heterogeneous nature, the eye has been more difficult to recreate using these cells.

“Unlike other organs, the eye is more difficult to recreate in the lab due to the presence of heterogeneous cells in the eye,” says corresponding author of the study, Ryuhei Hayashi. “The goal of our study was to develop a novel human cellular eye model using hiPSCs that will help improve our understanding of how these different cell types develop to form the eye.”

To achieve their goal, the researchers established a reporter cell line by modifying hiPSCs using genome editing technology, such that the cells express the fluorescent protein eGFP whenever they express the protein PITX2. PITX2 is a transcriptional factor protein that plays a key role during embryonic development of several organs, including the eyes. In the eye, PITX2 is specifically expressed in what is called periocular mesenchyme (POM), a collection of cells that give rise to the cornea, as well as muscle cells and connective tissue within the eye. As a result, by using the genetically modified cells, the researchers were able to fluorescently label POM cells.

“We wanted to know whether our new cellular model was able to recreate elements of normal eye development and isolated POM cells for characterization,” says lead author of the study Toru Okubo.

The researchers first showed that the modified hiPSCs remained pluripotent after genome editing, so they still maintained the properties of pluripotent stem cells in the same way as unchanged hiPSCs. They then induced the development of POM cells from hiPSCs and showed that they formed so-called self-formed ectodermal autonomous multi-zones (SEAM), which are two-dimensional tissues consisting of different eye cells that form during normal eye development (first reported by Hayashi’s group in 2016). Previously, there were no methods to isolate POM cells, but this new generation of gene-edited iPSCs enables the team to isolate POM cells selectively from the SEAM. By isolating the fluorescent POM cells from other, non-fluorescent cells, the researchers were then able to show that POM cells maintained known molecular markers during further cell culture, validating the recreation of eye development using their hiPSC reporter cell line.

“These are striking results that show how human stem cells can be used to study development and disease processes,” says Hayashi. “Our model could offer a new opportunity to understand how different aspects of eye development happen.”

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Materials provided by Osaka University. Note: Content may be edited for style and length.

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For clogged and hardened hearts, a mussel is the solution — ScienceDaily

Early mortality of myocardial infarction (MI), one of fatal diseases, is about 30%. So, it is critical to have immediate and proactive treatment to prevent a heart attack. Contributing to developing an efficient treatment of this fatal disease, a research team from South Korea recently proposed an effective stem cell treatment system for myocardial infarction, using harmless protein from mussel and stem cells.

Prof. Hyung Joon Cha and Mr. Tae Yoon Park from Department of Chemical Engineering, POSTECH with Prof. Sung Bo Sim from Department of Thoracic and Cardiovascular Surgery, Yeouido St. Mary’s Hospital and Prof. Jongho Lee from Department of Thoracic and Cardiovascular Surgery, Daejeon St. Mary’s Hospital developed an ‘adhesive protein-based immiscible condensed liquid system’ (APICLS) that efficiently delivered the mesenchymal stem cells (MSCs) to the damaged cardiac muscular tissues and enabled the transplantation prolonged. By employing the phase separation phenomenon of mussel adhesive protein, they were able to easily encapsulate the MSCs in the liquid coacervate. Especially, based on the mass production of bioengineered mussel adhesive protein, their newly suggested platform can be expected to be an innovative therapeutic system for myocardial infarction.

Heart is a vital organ that circulates blood while repeating contraction and relaxation of muscles by electrical signals. When blood vessels are clogged, oxygens and nutrients cannot be supplied to the heart and it brings severe damages to a muscle of the heart, causing infarcted myocardium with disruption of blood networks. This causes a necrosis on wall of the myocardium, resulting in cardiac wall thinning and this phenomenon is known as myocardial infarction. Because the heart cannot regenerate itself when it is damaged, there is no method for innovatively regenerating damaged heart muscles. As current therapeutic strategies, patients are treated with either mechanical device or heart transplantation.

Recently, there have been numbers of research proposing on transplanting exogenous stem cells into the damaged myocardium to help heart regeneration as a future treatment technique. However, transplanted stem cells have very low survival rate due to harsh environment of the heart. Even when the transplantation is successful, most of the stems cells soon die.

For a successful stem cell therapy on MI, there are two conditions required to survive in harsh environment of the damaged heart. First, the stem cells must be efficiently transplanted and remained into the thinned cardiac muscles. Secondly, transplanted stem cells must integrate rapidly into resident surrounding tissues to improve their viability by forming blood vessels. However, the current therapeutic methods so far cannot deliver injected stem cells to infarcted cardiac muscular tissues successfully, making it very difficult to maintain the transplantation.

The joint research team injected the MSCs encapsulated in APICLS into the thinned and infarcted cardiac muscular wall efficiently. They demonstrated in vivo feasibility through rat MI model that transplanted MSCs survived in the infarcted cardiac muscular tissues for a long time due to the mussel adhesive proteins with its unique characteristics of adhesiveness and angiogenesis and the efficacy of MSCs. Furthermore, the damaged heart muscles formed new blood vessels, prevented further apoptosis of existing cardiomyocytes, and regenerated the damaged cardiac wall by reducing fibrosis.

It is anticipated that the new stem cell delivery system proposed in this research will play an essential role in the stem cell therapeutic market as it used biocompatible materials which are harmless to humans.

“By using mussel adhesive proteins, we demonstrated with the MI rat model and proved its therapeutic efficacy as an efficient stem cell injection strategy. We gives a hope that it can also be successfully applied to chronic diseases and ischemic diseases that have similar environment,” said Prof. Hyung Joon Cha who led the research.

In the meanwhile, this research was introduced as the most innovative technology found by POSTECH in the Most Innovative Universities 2019 by Reuters last year. It is also published on the website of Journal of Controlled Release, the world’s most renowned journal in the field of drug delivery. This study was supported by the Marine BioMaterials Research Center grant funded by the Ministry of Oceans and Fisheries, Korea.

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New in vivo priming strategy to train stem cells can enhance cardiac repair effectiveness — ScienceDaily

Human stem cells have been regarded as one of the promising cell sources for cardiac regeneration therapy. But their clinical use is hampered due to the poor performance after transplantation into failing hearts. Recently a stem cell biologist from City University of Hong Kong (CityU), together with his collaborators, has developed a novel strategy, called in vivo priming, to “train” the stem cells to stay strong after implantation to the damaged heart via the 3D-printed bandage-like patch. The positive results of the study show that an in vivo priming strategy can be an effective means to enhance cardiac repair.

Dr Ban Kiwon, Assistant Professor of CityU’s Department of Biomedical Sciences, collaborated with cardiologist and experts in 3D printing from South Korea in achieving this breakthrough. Their findings were published in the latest issue of the scientific journal Science Advances, titled “In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair.”

Harsh environment in failing hearts hinders stem cell survival

One of the proposed approaches to treat myocardial infarction, commonly known as heart attack, with regeneration therapy is to inject the human stem cells directly into the failing hearts. In particular, human mesenchymal stem cells (hMSCs) have been considered as a competitive agent for clinical uses for their proven safety and significant paracrine effects supporting new blood vessel formation and inhibiting cell death. However, “the clinical trial results are disappointing as the micro-environment of a failing heart is very harsh for the injected hMSCs to stay alive,” said Dr Ban.

Therefore researchers have been exploring ways to increase the survival rate of hMSCs in failing hearts. “Priming, or called preconditioning, is a common strategy to empower the cells. The cells are educated through certain stimulations, and when they are relocated to tough environments, they are much stronger against bad condition and they will know how to react because of their previous experiences,” explained Dr Ban.

Conventionally, priming is performed in vitro (outside a living organism) before the cells are transplanted into the heart. “But the effects of priming done in this way usually last for two or three days only. To extend the duration of the priming effect, I have come up with an idea of ‘in vivo priming’, which means the hMSCs are primed directly on the failing hearts,” said Dr Ban.

Novel strategy: in vivo priming of hMSCs

To prove the concept, the research team loaded two types of MSCs into a tailor-made 3D-printed patch, namely the human bone marrow-derived MSCs, and the genetically engineered MSCs which have human hepatocyte growth factor protein. Hepatocyte growth factor (HGF) is involved in multiple biological activities, such as cell survival, blood vessel formation, anti-fibrotic activities, and important in adult organ regeneration and wound healing.

The patch, like a bandage, was then implanted on the top of the infarct area of the myocardial-infarction-induced heart of rats. “The genetically engineered MSCs can continuously secret human HGF protein to prime the hMSCs within the patch and make them ‘stronger’,” said Dr Ban.

Instead of directly injecting the genetically engineered cells into the heart, he added that encapsulating the cells in the patch for putting on the surface of the heart can help prevent mutation or other undesirable outcomes. And the patch is fabricated by 3D-printing of pig heart-derived extracellular matrix hydrogel, simulating the cardiac tissue-specific micro-environment.

It was found that the primed hMSCs had a higher survival rate compared with unprimed ones in the patches attached to the failing hearts. Those empowered hMSCs released greater amounts of paracrine factors beneficial for repairing damaged cardiac muscle tissues and regenerating vasculatures.

“We found that the primed cells can survive even after 8 weeks in the patch after implantation to the heart. Also, there is a significant improvement in cardiac function as well as vessel regeneration comparing to the unprimed cells,” said Dr Ban.

Great improvement of the priming effect

“Our team is the very first to achieve priming in hearts in vivo. But more importantly, by showing that in vivo priming of hMSCs can enhance the therapeutic potential for cardiac repair, we hope our study can bring significant implications for related stem cell therapy in future,” concluded Dr Ban. It took the team over two years to achieve these remarkable results. The team will explore the possibility of conducting the experiments on bigger animals and even clinical trials, as well as modifying the structure of the patch.

Dr Ban, Dr Jang Jinah from Pohang University of Science and Technology, as well as Professor Park Hun-Jun from The Catholic University of Korea are the leading authors of the paper. Mr Lee Sunghun, a PhD student from Department of Biomedical Sciences at CityU also participated in this research.

The study was supported by CityU, Hong Kong Research Grants Council, National Research Foundation of Korea, Ministry of Education as well as the Ministry of Science and ICT in South Korea.

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A ‘cardiac patch with bioink’ developed to repair heart — ScienceDaily

The heart is the driving force of circulating blood in the body and pumps blood to the entire body by repeating contraction and relaxation of the heart muscles continuously. Human stem cells are used in the clinical therapies of a dead heart, which happens when a blood vessel is clogged or whole or a part of heart muscles is damaged. The clinical use of human bone marrow-derived mesenchymal stem cells (BM-MSCs) have been expanded but failure of the transplanted stem cells in the heart still remains a problem. Recently, an international joint research team of POSTECH, Seoul St. Mary’s Hospital, and City University of Hong Kong developed a ‘cardiac patch with bioink’ that enhanced the functionality of stem cells to regenerate blood vessels, which in turn improved the myocardial infarction affected area.

The joint research team consisted of Prof. Jinah Jang and Dr. Sanskrita Das of POSTECH Creative IT Engineering, Mr. Seungman Jung of POSTECH School of Interdisciplinary Bioscience and Bioengineering, Prof. Hun-Jun Park, Mr. Bong-Woo Park, and Ms. Soo-Hyun Jung of The Catholic University, and Prof. Kiwon Ban and his fellows from City University of Hong Kong. The team mixed genetically engineered stem cells (genetically engineered hepatocyte growth factor-expressing MSCs, HGF-eMSCs) developed by SL Bigen. Co., Ltd to make bioink in the form of a patch and introduced a new therapy by transplanting it to a damaged heart. They called this new strategy as ‘in vivo priming’. The name came from the principle that maximized function of mesenchymal stem cells are maintained in vivo as well as through its exposure to the growth factor secreted by the genetically engineered stem cells.

The joint research team first genetically engineered the existing BM-MSCs to produce hepatocyte growth factor consistently to improve the therapeutic potential of stem cells. The engineered stem cells (HGF-eMSCs) were then mixed with BM-MSCs to make the bioink. They transplanted the cardiac patch with this bioink to the heart muscles affected by myocardial infarction. Considering the limited amount of cells that could be transferred, they used heart-derived extracellular matrix bioink to make a cardiac patch.

Implanted cells in a patch survived longer in vivo and had more myocardiocytes survived than the only BM-MSCs transplanted experimental group. This was because the secretion of cytokine, which helps formation of blood vessels and cell growth was maximized and delivered nutrients fluently that promoted vascular regeneration and enhanced survival of the myocardiocytes.

The research team anticipated that this new method could be a breakthrough treatment of myocardial infarction as the implanted stem cells through HGF-eMSCs ultimately enhanced vascular regeneration and improved the myocardial infarction affected area.

“We can augment the function of adult stem cells approved by Ministry of Food and Drug Safety and FDA using this newly developed and promising 3D bioprinting technology with the engineered stem cells. It is our goal to develop a new concept of medicine for myocardial infarction in the near future,” said Prof. Jinah Jang who led the research.

POSTECH began to develop medicine for cardiovascular diseases based on this newly developed bioprinting method with the research team from The Catholic University in 2017. Now, it is being tested in animals for efficacy evaluation with Chonnam National University. Also, the technology is already transferred to T&R Biofab, which is a company developing 3D printers, software, and bioinks to print cells.

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Materials provided by Pohang University of Science & Technology (POSTECH). Note: Content may be edited for style and length.

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Advances in production of retinal cells for treating blindness — ScienceDaily

Researchers at Karolinska Institutet and St Erik Eye Hospital in Sweden have discovered a way to refine the production of retinal cells from embryonic stem cells for treating blindness in the elderly. Using the CRISPR/Cas9 gene editing, they have also managed to modify the cells so that they can hide from the immune system to prevent rejection. The studies are published in the scientific journals Nature Communications and Stem Cell Reports.

Age-related macular degeneration of the eye is the most common cause of blindness in the elderly. This loss of vision is caused by the death of the photoreceptors (the rods and cones) resulting from the degeneration and death of the underlying retinal pigment epithelial (RPE cells), which provide the rods and cones vital nourishment. A possible future treatment could be to transplant fresh RPE cells formed from embryonic stem cells.

Working with colleagues at St Erik Eye Hospital, researchers at Karolinska Institutet have now found specific markers on the surface of the RPE cells that can be used to isolate and purify these retinal cells. The results are published in Nature Communications.

“The finding has enabled us to develop a robust protocol that ensures that the differentiation of embryonic stem cells into RPE cells is effective and that there is no contamination of other cell types,” says principal investigator Fredrik Lanner, researcher at the Department of Clinical Science, Intervention and Technology and the Ming Wai Lau Center for Reparative Medicine at Karolinska Institutet. “We’ve now begun the production of RPE cells in accordance with our new protocol for the first clinical study, which is planned for the coming years.”

One obstacle when transplanting tissue generated from stem cells is the risk of rejection, which occurs if transplantation antigens of the donor and patient tissue differ. Research groups around the world are therefore working on creating what are known as universal cells, which ideally will not trigger an immune response.

In a study published in Stem Cell Reports the same group at Karolinska Institutet created embryonic stem cells able to hide from the immune system. Using CRISPR/Cas9 gene editing, they removed certain molecules, HLA class I and class II, which sit on the surface of the stem cells as a means by which the immune system can identify them as endogenous or not. The stem cells lacking these molecules were then differentiated into RPE cells.

The researchers have been able to show that the modified RPE cells retain their character, that no harmful mutations appear in the process and that the cells can avoid the immune system’s T cells without activating other immune cells. The rejection response was also significantly less and more delayed than after the transplantation of regular RPE cells, the surfaces of which still possess HLA molecules.

“The research is still in an early stage, but this can be an important initial step towards creating universal RPE cells for the future treatment of age-related macular degeneration,” says joint last author Anders Kvanta, adjunct professor at the Department of Clinical Neuroscience and consultant at St Erik Eye Hospital.

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Scientists explore newborn, regenerated neurons — ScienceDaily

The zebrafish is a master of regeneration: If brain cells are lost due to injury or disease, it can simply reproduce them — contrary to humans where this only happens in the fetal stage. However, the zebrafish is evolutionarily related to humans and, thus, possesses the same brain cell types as humans. Can a hidden regeneration potential also be activated in humans? Are therapies for stroke, craniocerebral trauma and presently incurable diseases such as Alzheimer’s and Parkinson’s possible?

Dresden scientists have succeeded in determining the number and type of newly formed neurons in zebrafish; practically conducting a “census” in their brains. Following an injury, zebrafish form new neurons in high numbers and integrate them into the nervous system, which is the reason for their amazing brain regeneration ability. The study was conducted as a collaboration project “made in Dresden”: Scientists from the Center for Regenerative Therapies TU Dresden (CRTD) combined their expertise in stem cell biology with the latest methods from the DRESDEN-concept Genome Center and complex bio-informatic analyses from the Max Planck Institute for the Physics of Complex Systems and the Center for Systems Biology Dresden. They have now published their results in the scientific journal DEVELOPMENT, which reports on topics of developmental, stem cell and regenerative biology.

For their study, the team led by Dr. Christian Lange and Prof. Dr. Michael Brand from the CRTD used adult transgenic zebrafish in whose forebrain they were able to identify the newborn neurons. The forebrain of the zebrafish is the equivalent to the human cerebral cortex, the largest and functionally most important part of the brain. The Dresden research team investigated the newborn and mature neurons as well as brain stem cells using single cell sequencing. Thus, they discovered specific markers for newborn neurons and were able to comprehensively analyse which types of neurons are newly formed in the adult brain of the zebrafish.

The scientists discovered two types of neurons that can be newly formed: Projection neurons, which create connections between brain areas, and internal neurons, which serve to fine-tune the activity of the projection neurons. The researchers also investigated the data obtained from brain cell sequencing of mice and found that zebrafish and mice have the same cell types. This also makes these results highly relevant for humans.

“On the basis of this study, we will further investigate the regeneration processes that take place in zebrafish. In particular, we will study the formation of new neurons after traumatic brain damage and their integration,” explains Prof. Dr. Michael Brand, CRTD Director and senior author of the study. “We hope to gain insights that are relevant for possible therapies helping people after injuries and strokes or suffering from neurodegenerative diseases. We already know that a certain regenerative ability is also present in humans and we are working on awakening this potential. The results of our study are also important for understanding the conditions under which transplanted neurons can network with the existing ones and thus could let humans re-gain their former mental performance.”

The CRTD at TU Dresden is the academic home for scientists from more than 30 nations. Their mission is to discover the principles of cell and tissue regeneration and leveraging this for recognition, treatment and reversal of diseases. The CRTD links the bench to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene-editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, haematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases. The group of Prof. Dr. Michael Brand investigates the patterning and regeneration of the vertebrate brain and eye.

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New mechanism for regulating the activity of stem cells discovered — ScienceDaily

Scientists from the German Cancer Research Center (DKFZ) and the Heidelberg Institute of Stem Cell Technology and Experimental Medicine (HI-STEM) and the Max Planck Institute in Freiburg have identified a new control mechanism that enables stem cells to adapt their activity in emergency situations. For this purpose, the stem cells simultaneously modify the blueprints for hundreds of proteins encoded in the gene transcripts. In this way, they control the amount of protein produced and can also control the formation of certain proteinisoforms. If this mechanism is inactivated, stem cells lose their self-renewal potential and can no longer react adequately to danger signals or inflammation.

Messenger RNA molecules (mRNAs), the transcripts of genes, serve as the blueprint for the construction of proteins. In all higher organisms, the cell attaches a long chain of adenine nucleotides, the so-called poly(A) tail, to the rear end of the transcripts in a process known as polyadenylation. The length and position of the chain varies from organism to organism and serves to stabilize the RNA molecule.

Different signaling motifs show the participating enzymes the site where the poly(A) chain is to be attached to the transcript. This does not always happen at the same site of the mRNA. The differential use of these sites is known as “alternative polyadenylation.” This mechanism affects the length of the so-called 3′-untranslated end of the mRNA, a region that contains information beyond the protein sequence. This 3′-untranslated region is particularly important for stability, localisation and the efficiency with which the transcripts are translated into proteins. “Only recently it has been known that some cell types use this mechanism to control how much protein is produced per transcript and which isoform is to be expressed,” says Pia Sommerkamp, the lead author of the study conducted by DKFZ and HI-STEM.

By applying a novel sequencing method, the scientists were able to identify numerous genes that are essential for stem cell development and are regulated via alternative polyadenylation during differentiation or in response to inflammation. These include the central metabolic enzyme glutaminase, which can be produced in two differently active isoforms. As the researchers found out, the activation of blood stem cells leads to a change from the less active to the highly active glutaminase isoform. This switch is coordinated by alternative polyadenylation.

“Only this isoform switch enables the stem cells to adapt all the necessary metabolic pathways according to their needs. This includes rapid increases in activity that are necessary in the case of infections or inflammations,” explains Nina Cabezas-Wallscheid, who was co-supervisor of the study at the MPI in Freiburg. “With alternative polyadenylation, we have now discovered another control level with which stem cells regulate vital processes. We now want to investigate in more detail whether cancer stem cells also use this mechanism for their own purposes in leukemias. We hope that this will provide us with new approaches for fighting the disease,” explains Andreas Trumpp, Director of HI-STEM gGmbH at DKFZ and senior author of the study.

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Human immune cells produced in a dish in world first — ScienceDaily

One day the advance could lead to a patient’s own skin cells being used to produce new cells for cancer immunotherapy or to test autoimmune disease interventions.

The group, led by Professors Ed Stanley and Andrew Elefanty, from the Murdoch Children’s Research Institute in Melbourne, Australia, said the work has added definitive evidence about how the body’s earliest immune cells are formed.

These lymphocytes are produced by cells which form the embryo’s first organs rather than the blood-producing stem cells that sit inside the body’s bone marrow.

The research combined two powerful laboratory techniques, genetic engineering and a novel way of growing stem cells, to make the breakthrough, which has been published in the  journal Nature Cell Biology.

First, the team engineered pluripotent stem cells to glow green when a specific protein marker of early immune cells, RAG1, was switched on. RAG1 is responsible for creating the immune response to infections and vaccines.

Next, the team isolated the glowing green RAG1-positive cells and showed that they could also form multiple immune cell types, including cells required for shaping the development of the whole immune system.

“We think these early cells might be important for the correct maturation of the thymus, the organ that acts as a nursery for T-cells” said Professor Stanley.

“These RAG1 cells are like the painters and decorators who set up that nursery, making it a safe and cozy environment for later-born immune cells,” he said.

Professor Elefanty said, “Although a clinical application is likely still years away, we can use this new knowledge to test ideas about how diseases like childhood leukemia and type 1 diabetes develop. Understanding more about the steps these cells go through, and how we can more efficiently nudge them down a desired pathway, is going to be crucial to that process.”

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