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Surprisingly simple method could provide a new tool for producing specialized cytoplasm for reproductive medicine — ScienceDaily

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In a new study published in the journal Nature, researchers in Japan report that activating just eight genes for producing gene-controlling proteins is enough to convert mouse stem cells directly into oocyte-like cells that mature and can even be fertilized like egg cells.

On top of providing new insights into the mechanisms of egg cell development, the research may lead to a simple route for generating highly specialized substances unique to oocytes for use in reproductive biology and medicine.

Stored in the body until they mature into egg cells ready for fertilization, oocytes represent the very first step in the creation a new human life.

Oocytes are extremely unique because of their ability to bring forth the over two hundred kinds of highly differentiated cells needed to create an individual person, and one key to this ability is the complex mixture of substances within the fluid-like cytoplasm filling the cells.

So extraordinary are oocytes and their cytoplasm that replacing an oocyte’s DNA-containing nucleus with that of a body cell — a process called somatic cell nuclear transfer — can produce a new life, as famously demonstrated with Dolly the sheep.

Thus, a fundamental understanding of oocytes and their development is important for both advancing reproductive medicine and better grasping how life propagates, but knowledge of the many genes that orchestrate oocyte development is still far from complete.

Analyzing the development of oocytes from mice, researchers led by Katsuhiko Hayashi, professor at Kyushu University’s Faculty of Medical Sciences, have now identified eight genes for gene-triggering proteins known as transcription factors that not only are necessary for oocyte growth but also can directly convert mouse stem cells into oocyte-like cells.

“I was initially in complete disbelief to see mouse stem cells so quickly and easily take the form of oocytes based on introducing just a handful of factors, but repeated experiments proved it was true,” says Nobuhiko Hamazaki, first author on the study reporting the results and assistant professor at Kyushu University at the time of the research. “To find that eight transcription factors could lead to such big changes was quite astonishing.”

Working in collaboration with researchers at RIKEN, Hayashi’s group found that both mouse embryonic stem cells and induced pluripotent stem (iPS) cells — which can be created from adult body cells — consistently converted into oocyte-like cells when forced to produce the set of eight transcription factors, with only four factors being sufficient in some cases though with worse reproducibility.

“That stem cells can be directly converted into oocyte-like cells without following the same sequence of steps that happen naturally is remarkable,” says Hayashi.

When grown in the presence of other cells usually found around oocytes, the oocyte-like cells developed structures similar to mature egg cells but with an abnormal chromosome structure. Despite this, the mature oocyte-like cells could be fertilized in vitro and exhibited early development, with some even progressing to an eight-cell stage.

Though the modified nuclei of the oocyte-like cells may not be useable in the long run, this is no problem for applications needing mainly the oocyte cytoplasm, such as for studies of reproductive biology and for treatments like mitochondrial replacement therapy, in which parts of oocytes are replaced to prevent mothers from passing to their children diseases related to the mitochondria.

“Cytoplasm from oocytes is an invaluable resource in reproductive biology and medicine, and this method could provide a novel tool for producing large amounts of it without any invasive procedures,” comments Hayashi. “While the processes could still be much more complex for humans, these initial results in mice are very promising.”

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Scientists modified ‘mesenchymal stem cells’ to carry anti-cancer drugs and deliver them to target cancers — ScienceDaily

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As humans evolve, cancer also evolves in parallel, making the race for finding efficient treatment methods for cancer patients challenging and constant. In addition to designing drugs for treatment, the delivery of these drugs to targeted organs is also a major challenge faced by the cancer research community.

Many research groups have tried to develop techniques to efficiently deliver anti-cancer drugs to tumors. An interesting way utilizes a distinct group of cells in our body, the mesenchymal stem cells (MSCs), which have a special ability to find and move towards tumors. This means that theoretically, we can load these “tumor-homing” MSCs with anti-cancer drugs and use them to hinder cancer progression. However, pilot studies show that the anti-cancer drug loading capacity of MSCs is limited, and they tend to lose their ability to target and reach tumor cells upon drug loading.

In a recent study published in Journal of Controlled Release, researchers from Japan, led by Dr. Kosuke Kusamori and Professor Makiya Nishikawa from Tokyo University of Science, sought to find out how to modify MSCs to bypass these problems. Dr. Kusamori, Assistant Professor in the University’s Department of Pharmacy says, “We wondered if the answer to our dilemma of modifying mesenchymal stem cells with an anticancer drug was to exploit the property of mesenchymal stem cells to accumulate in tumor tissues.”

Using the well-known “avidin-biotin complex” (ABC) method, the researchers used liposomes — cellular lipid bags popularly used as drug delivery systems — to carry the anti-cancer drug doxorubicin (DOX) to the surface of specific mouse MSCs. They named these lipid bags carrying DOX “DOX-Lips.”

The researchers found that the MSCs loaded with DOX-Lips could carry and selectively target mouse colon cancer cells growing in artificial cultures in the lab. These modified MSCs could not only carry a significant amount of the drug, but also efficiently deliver it inside the target cancer cells. To test if this feature is replicated in a living system, they used a mouse model with skin and lung cancer. They found that in both cases, DOX-Lips were able to efficiently reach cancer cells and release the drug into the cytoplasm of the cancer cells. The researchers concluded that the modified MSCs could completely suppress tumor growth in mouse models.

There are several advantages to this new method. First, the process is relatively faster than previously known methods. As Yukiya Takayama, a doctoral student in Professor Nishikawa’s lab and a co-author of the study observes, “The relatively short duration of the ABC method made it possible to quickly modify the cell surface with DOX-Lips and avoid cell damage.” Second, this method did not affect the process of cell attachment to cancer cells, thereby ensuring maximum efficiency in drug delivery. Third, contrary to previous observations that lipid bags of only a certain size can be used to deliver drugs, this new study suggests that the size of the lipid bags very likely does not affect drug delivery; this finding can be exploited to deliver many different doses of drugs as well.

The combination of the ABC method and the use of Lips thus seems to be the answer to the researchers’ dilemma. Professor Nishikawa is excited about these results. “We have succeeded in developing a new targeted cancer therapy,” he observes. “Mesenchymal stem cells can migrate to brain tumors and minute cancer lesions that are otherwise inaccessible to conventional drug delivery systems. Our method may thus be effective against intractable cancers,” Nishikawa says.

This study is thus a promising advancement in the field of cancer research; the new method identified by the researchers may prove to be the answer on how to send the treating drug to cancer’s doorstep.

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Research dispels fears human stem cells contain cancer-causing mutations — ScienceDaily

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Pioneering new research has made a pivotal breakthrough that dispel concerns that human stem cells could contain cancer-causing mutations.

A team of scientists from the University of Exeter’s flagship Living Systems Institute has shown that stem cells contain no cancer mutations when they are grown in their most primitive or naïve state.

The ground-breaking advances made by the research team should help allay fears surrounding recent controversy about the genetic stability of human embryonic stem cells.

The study is published in the peer-reviewed journal Cell Stem Cell on Monday, December 14th 2020.

Human embryonic stem cells offer great promise for regenerative medicine because they can be turned into every type of cell in our bodies — such as neurons, heart, pancreatic, and liver cells.

As a result, they represent a significant potential source of cells that could be used to replace those lost through damage or disease.

A major concern, however, had been whether embryonic stem cells acquire cancer-causing mutations.

Recent studies had indicated that human pluripotent stem cells had shown the potential for increased frequency of serious cancer-causing mutations.

However, the new research, led by Senior Research Fellow Dr Ge Guo from the University of Exeter has shown that there is no increased frequency of mutations in cancer-related genes found in these cells.

Analysing RNA-sequencing data from human naïve pluripotent stem calls, the research team found that the actual incidence of cancer-causing mutations were closer to zero.

Dr Guo, who has pioneered research into human naïve embryonic stem cells and is part of the University of Exeter’s College of Medicine and Health said: “Our study corrects misinformation in the field and encourages us to continue exploring the potential of naïve stem cells.”

Professor Austin Smith co-author of the paper and Director of the Living Systems Institute added: “I am delighted to see Dr Guo launch her team in LSI by publishing these significant results.”

Dr Guo’s research is focussed on mammalian pluripotent stem cells and cell fate transition during early embryo development.

Key research areas in the lab include understanding the developmental plasticity of human naïve stem cells; Modelling early human embryo development ex vivo by reconstruction of embryo structures; and establishing pluripotent stem cells from various mammalian species and elucidation of shared and distinct gene regulatory features.

The research was funded by the Medical Research Council.

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Development of new stem cell type may lead to advances in regenerative medicine — ScienceDaily

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A team led by UT Southwestern has derived a new “intermediate” embryonic stem cell type from multiple species that can contribute to chimeras and create precursors to sperm and eggs in a culture dish.

The findings, published online this week in Cell Stem Cell, could lead to a host of advances in basic biology, regenerative medicine, and reproductive technology.

Cells in early embryos have a range of distinct pluripotency programs, all of which endow the cells to create various tissue types in the body, explains study leader Jun Wu, Ph.D., assistant professor of molecular biology. A wealth of previous research has focused on developing and characterizing “naïve” embryonic stem cells (those about four days post-fertilization in mice) and “primed” epiblast stem cells (about seven days post-fertilization in mice, shortly after the embryo implants into the uterus).

However, says Wu, there’s been little progress in deriving and characterizing pluripotent stem cells (PSCs) that exist between these two stages — largely because researchers have not been able to develop a paradigm for maintaining cells in this intermediate state. Cells in this state have been thought to possess unique properties: the ability to contribute to intraspecies chimeras (organisms that contain a mix of cells from different individuals of the same species) or interspecies chimeras (organisms that contain a mix of cells from different species) and the ability to differentiate into primordial germ cells in culture, the precursors to sperm and eggs.

For this study, the researchers successfully created intermediate PSCs, which they named “XPSCs” from mice, horses, and humans.

Wu says that these results could eventually lead to an array of advances in both basic and applied research. For example, looking at gene activity in XPSCs from different species and interspecies chimeras could help researchers understand which signatures have been conserved through evolution. Examining the communication between cells in chimeras may help scientists identify strategies that could be used to accelerate the development of tissues and organs from stem cells used for transplantation. And using chimera-derived primordial germ cells to create sperm and eggs could aid in preserving endangered animal species and advancing infertility treatments.

“These XPSCs have enormous potential. Our study helps open the door to each of these possibilities,” says Wu, who is a Virginia Murchison Linthicum Scholar in Medical Research.

Wu notes that developing XPSCs presented a special challenge because the conditions that keep naïve PSCs in a stable state are exactly the opposite from those that stabilize primed PSCs. While culture conditions for naïve PSCs must activate a WNT cell-signaling pathway and suppress the FGF and TGF-ß pathways, the conditions to maintain primed PSCs must suppress WNT and activate FGF and TGF-ß.

Aiming for the preferred environment for XPSC derivation, Wu and his colleagues placed cells from early mouse embryos into cultures containing chemicals and growth factors that activate all three pathways. These lab-grown cells were extremely stable in culture and able to multiply without developing any further for approximately two years.

Additional experiments showed that these cells met the expectations researchers have long strived to meet of contributing to chimeras and directly differentiating into primordial germ cells. Wu and his colleagues made intraspecies chimeras of mice using cells derived from mice with different coat colors by injecting the cells into early mouse embryos. They also tracked the contributions of the XPSCs by tagging the cells with a fluorescent protein and then identifying them throughout the resulting offspring’s body.

Wu’s team made interspecies chimeras by injecting horse XPSCs into early mouse embryos and allowing the embryos to develop in mice for several days. Surprisingly, although horses have a comparatively long gestational period — nearly a year — the researchers found that these foreign cells had contributed to mouse organ development, indicating that signals from the mouse cells determine organ developmental timelines.

Like XPSCs from other species, the human cells showed that they were capable of differentiating into a variety of tissues if culture conditions allowed them to progress in development, as well as directly form primordial germ cells in a dish.

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Tagging produces detailed catalog of transcription factors key to making each cell type — ScienceDaily

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A team of biomedical engineers at Duke University has created a new way to turn stem cells into a desired cell type by mastering the language of gene regulatory networks.

Programming stem cells into other cell types is not a new idea. Several methods already exist, but the results have left something to be desired. Often, programmed stem cells do not mature correctly when cultured in the lab, so researchers seeking adult neuron cells for an experiment might end up with embryonic neurons, which won’t be able to model late-onset psychiatric and neurodegenerative conditions.

“The cells might seem right at first glance,” said Josh Black, the Duke Ph.D. student who led the work in Charles Gersbach’s lab, “but they are often missing some of the key properties you want in those cells.”

Using CRISP gene editing, the lab led by Gersbach, The Rooney Family Associate Professor of Biomedical Engineering and the Director of the Center for Advanced Genomic Technologies, created a method to identify which transcription factors — master controllers of gene activity — were essential to making a good neuron.

Their work, appearing Dec. 1 in Cell Reports, demonstrates the potential of the approach to make mature adult neurons, but it could be applied to program any cell type.

CRISPR technology is most often used for editing DNA sequences, known as “genome editing,” in which the Cas9 protein is bound to a guide RNA that directs Cas9 to cut the DNA at a specific location, leading to changes in the DNA sequence. “DNA editing has been widely used to alter gene sequences, but that doesn’t help in situations where the gene is turned off,” Gersbach said.

A deactivated Cas9 (dCas9) protein, though, will attach to the DNA without cutting it. In fact, it typically won’t do anything without another molecule attached or recruited to it. Gersbach and his colleagues have previously reported a variety of methods to attach different molecular domains to the dCas9 protein can that will tell a cell to turn on a gene and remodel chromatin structure.

When Black joined Gersbach’s lab, he was interested in using these tools to turn on genes that could convert one cell type into another to create better disease models.

In 2016, Black and Gersbach reported an approach to use the CRISPR-based gene activators to turn on gene networks that would convert fibroblasts, an easily accessible cell type that makes up connective tissue, to neuronal cells. This study targeted gene networks that were known to be associated with neuronal specification, but did not generate cells with all of the properties needed to make effective disease models. However, the right gene networks to generate those desired cells were unknown, and there are were thousands of possibilities encoded in the human genome. So Black and Gersbach devised a strategy to test all of the networks in a single experiment.

They started with pluripotent stem cells, since this cell type should be able to become any other cell in the human body. To make mature neurons from stem cells, the team engineered stem cells that fluoresced red once they became neuronal. The brighter the fluorescence, the stronger the push towards a neuronal fate. Then they made a pooled library of thousands of guide RNAs targeted to all of the genes that encode transcription factors in the human genome. Transcription factors are the master regulators of gene networks, so to make the desired neurons, they have to get all of the right transcription factors turned on.

They introduced the CRISPR gene activator and guide RNA library into the stem cells so that each cell only received a single guide RNA, and therefore turned on its particular corresponding transcription factor gene target. Then they sorted the cells based on how red they became and sequenced the guide RNAs in the most and least red cells, which told them which genes, when turned on, made the cells more or less neuronal.

When they profiled the gene expression from the stem cells engineered with the guide RNAs, the results suggested that the corresponding cells generated more specific and more mature types of neurons. They also found genes that worked together when targeted simultaneously. Moreover, the experiment revealed factors that antagonized the neuronal commitment of the stem cells, and when they used CRISPR-based repressors of those genes, they could also enhance the neuronal specification.

However, these results were all just measuring markers of neurons. To know if these engineered cells truly recapitulated the function of more mature neurons, they needed to test their ability to transmit electrical signals.

For this, they turned to Professor Scott Soderling, the George Barth Geller Distinguished Professor for Research in Molecular Biology and Chair of the Duke Department of Cell Biology. Shataakshi Dube, a grad student in Soderling’s lab, used a technique known as patch clamp electrophysiology to measure the electrical signals inside the newly formed neurons. By poking a tiny hole in the cell with a very small pipette, she could look inside the neuron and see if it was transmitting electrical signals known as action potentials. If so, the team knew the neuronal cell had properly matured. In fact, the neurons engineered to activate a particular pair of transcription factor genes were more functionally mature, emitting more action potentials more frequently.

“I was curious but skeptical on how neuronal these stem cells could become,” Dube said, “but it was remarkable to see how much these programmed cells looked just like normal neurons.”

The process from stem cell to mature neuronal cell took seven days, dramatically shortening the timeframe compared to other methods that take weeks or months. This faster timeline has the potential to significantly accelerate the development and testing of new therapies for neurological disorders.

Creating better cells will help researchers in a number of ways. Diseases like Alzheimer’s disease, Parkinson’s disease, and schizophrenia most often occur in adults and are difficult to study because making the right cells in the lab is challenging. This new method can allow researchers to better model these diseases and others. It can also help with drug screening, as different cells respond to drugs differently.

More broadly, the same method for screening transcription factor genes and gene networks could be used to improve methods to make any cell type, which could be transformative for regenerative medicine and cell therapy.

For example, Gersbach’s group reported a method for using CRISPR-based gene activation to convert human stem cells into muscle progenitor cells that could regenerate damaged skeletal muscle tissue earlier this year.

“The key to this work is developing methods to use the power and scalability of CRISPR-based DNA targeting to program any function into any cell type,” Gersbach said. “By leveraging the gene networks already encoded in our genome, our control over cell biology is dramatically improved.”

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Researchers harness 1732 transcription factors to obtain 290 new differentiation recipes — ScienceDaily

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Induced pluripotent stem cells (iPS) have the potential to convert into a wide variety of cell types and tissues for drug testing and cell replacement therapies. However, the “recipes” for this conversion are often complicated and difficult to implement. Researchers at the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden, Harvard University (USA) and the University of Bonn have found a way to systematically extract hundreds of different cells quickly and easily from iPS using transcription factors, including neurons, connective tissue and blood vessel cells. Researchers can use this transcription factor source through the non-profit organization Addgene. The results have now been published in the journal Nature Biotechnology.

The researchers used human induced pluripotent stem cells (iPS), which were reprogrammed from connective tissue cells into a quasi-embryonic state. In principle, iPS cells can be used to obtain all kinds of differentiated cells, from neurons to blood vessel cells, with each recipe being individually adapted. “Most differentiation protocols are very laborious and complicated. It’s not possible to obtain different cell types from iPS simultaneously and in a controlled manner in a single culture,” explains Prof. Dr. Volker Busskamp, who works at the Eye Clinic and the ImmunoSensation2 Cluster of Excellence at the University of Bonn the Excellence Cluster Physics of Life (PoL) and at the CRTD at TU Dresden.

Together with a team from Harvard University, TU Dresden and the University of Bonn, he aimed to replace the complicated procedures with simple “recipes.” Using a large-scale screening process, the researchers found a total of 290 DNA-binding proteins that quickly and efficiently reprogram stem cells into target cells. The researchers were able to demonstrate that just a single transcription factor is sufficient in each case to derive differentiated neurons, connective tissue, blood vessel and glial cells from the stem cells within four days. The latter coat neurons as “insulators.”

A genetic switchboard for stem cell differentiation

Using automated procedures, the researchers introduced the DNA sequence for the respective transcription factor and other control elements into the stem cell genome. The transcription factors could be activated by adding a small molecule, causing some of the transgenic stem cells to be converted into differentiated cells. It was then possible to distinguish and automatically sort stem cells and differentiated cells using cell markers. The researchers subsequently investigated how much of a certain transcription factor was present in the differentiated cells compared to the stem cells. “The greater the difference, the more important the respective transcription factor seems to be for the conversion of iPS into differentiated cells,” explains Busskamp.

The team used this method to test a total of 1732 potential transcription factors on three different stem cell lines. The researchers found an effect for 290 different transcription factors that caused the iPS to convert into differentiated cells. This is new territory, because this property of the iPS programming of 241 of the discovered transcription factors was previously unknown. Using the example of neurons, connective tissue, blood vessel and glial cells, the researchers performed various tests to show that the converted cells are very similar to human body cells in their functional ability.

The results open new possibilities in research

“The advantage of the identified transcription factors is that they are able to convert iPS into body cells particularly quickly and easily and that they can potentially also be used to form more complex tissues,” says Busskamp. What took weeks or even months now happens within days. Instead of costly and time-consuming protocols, a single transcription factor is sufficient for the hits identified in mass screening.

“These results open new possibilities,” says Prof. Dr. George M. Church of Harvard University. “The variety, simplicity and speed of stem cell programming using transcription factors makes stem cell research possible on a large scale. Worldwide, 50 other groups are already working with our programmable stem cell lines and with the transcription factor library.” The two lead authors Alex H.M. Ng and Parastoo Khoshaklagh from Harvard University have now founded the start-up GC Therapeutics in Cambridge (USA), which provides programmable stem cells with customized, integrated transcription factors.

“The cooperation between the different research institutions was very successful, because the different disciplines complemented and interlinked with each other very well,” says Busskamp. Researchers worldwide can now use the transcription factor resource that is available by the non-profit organization Addgene.

Particularly as an expert in degenerative retinal diseases, Busskamp sees great potential for stem cell technology in ophthalmology. “For diseases in which the retina degenerates, such as age-related macular degeneration (AMD), there is hope that at some point, it will be possible to replace the affected photoreceptors with the help of iPS conversion,” says Busskamp. “My team is working towards this goal.”

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Cutting edge technology to bioprint mini-kidneys — ScienceDaily

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Researchers have used cutting edge technology to bioprint miniature human kidneys in the lab, paving the way for new treatments for kidney failure and possibly lab-grown transplants.

The study, led by the Murdoch Children’s Research Institute (MCRI) and biotech company Organovo and published in Nature Materials, saw the research team also validate the use of 3D bioprinted human mini kidneys for screening of drug toxicity from a class of drugs known to cause kidney damage in people.

The research showed how 3D bioprinting of stem cells can produce large enough sheets of kidney tissue needed for transplants.

Like squeezing toothpaste out of a tube, extrusion-based 3D bioprinting uses a ‘bioink’ made from a stem cell paste, squeezed out through a computer-guided pipette to create artificial living tissue in a dish.

MCRI researchers teamed up with San Diego based Organovo Inc to create the mini organs.

MCRI Professor Melissa Little, a world leader in modelling the human kidney, first began growing kidney organoids in 2015. But this new bio-printing method is faster, more reliable and allows the whole process to be scaled up. 3D bioprinting could now create about 200 mini kidneys in 10 minutes without compromising quality, the study found.

From larger than a grain of rice to the size of a fingernail, bioprinted mini-kidneys fully resemble a regular-sized kidney, including the tiny tubes and blood vessels that form the organ’s filtering structures called nephrons.

Professor Little said by using mini-organs her team hope to screen drugs to find new treatments for kidney disease or to test if a new drug was likely to injure the kidney.

“Drug-induced injury to the kidney is a major side effect and difficult to predict using animal studies. Bioprinting human kidneys are a practical approach to testing for toxicity before use,” she said.

In this study, the toxicity of aminoglycosides, a class of antibiotics that commonly damage the kidney, were tested.

“We found increased death of particular types of cells in the kidneys treated with aminoglycosides,” Professor Little said.

“By generating stem cells from a patient with a genetic kidney disease, and then growing mini kidneys from them, also paves the way for tailoring treatment plans specific to each patient, which could be extended to a range of kidney diseases.”

Professor Little said the study showed growing human tissue from stem cells also brought the promise of bioengineered kidney tissue.

“3D bioprinting can generate larger amounts of kidney tissue but with precise manipulation of biophysical properties, including cell number and conformation, improving the outcome,” she said.

Currently, 1.5 million Australians are unaware they are living with early signs of kidney disease such as decreased urine output, fluid retention and shortness of breath.

Professor Little said prior to this study the possibility of using mini kidneys to generate transplantable tissue was too far away to contemplate.

“The pathway to renal replacement therapy using stem cell-derived kidney tissue will need a massive increase in the number of nephron structures present in the tissue to be transplanted,” she said.

“By using extrusion bioprinting, we improved the final nephron count, which will ultimately determine whether we can transplant these tissues into people.”

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Researchers uncover the unique way stem cells protect their chromosome ends — ScienceDaily

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Telomeres are specialised structures at the end of chromosomes which protect our DNA and ensure healthy division of cells. According to a new study from researchers at the Francis Crick Institute published in Nature, the mechanisms of telomere protection are surprisingly unique in stem cells.

For the last 20 years, researchers have been working to understand how telomeres protect chromosome ends from being incorrectly repaired and joined together because this has important implications for our understanding of cancer and aging.

In healthy cells, this protection is very efficient, but as we age our telomeres get progressively shorter, eventually becoming so short that they lose some of these protective functions. In healthy cells, this contributes to the progressive decline in our health and fitness as we age. Conversely, telomere shortening poses a protective barrier to tumour development, which cancer cells must solve in order to divide indefinitely.

In somatic cells, which are all the cells in the adult body except stem cells and gametes, we know that a protein called TRF2 helps to protect the telomere. It does this by binding to and stabilising a loop structure, called a t-loop, which masks the end of the chromosome. When the TRF2 protein is removed, these loops do not form and the chromosome ends fuse together, leading to “spaghetti chromosomes” and killing the cell.

However, in this latest study, Crick researchers have found that when the TRF2 protein is removed from mouse embryonic stem cells, t-loops continue to form, chromosome ends remain protected and the cells are largely unaffected.

As embryonic stem cells differentiate into somatic cells, this unique mechanism of end protection is lost and both t-loops and chromosome end protection become reliant on TRF2. This suggests that somatic and stem cells protect their chromosome ends in fundamentally different ways.

“Now we know that TRF2 isn’t needed for t-loop formation in stem cells, we infer there must be some other factor that does the same job or a different mechanism to stabilise t-loops in these cells, and we want to know what it is,” says Philip Ruis, first author of the paper and PhD student in the DNA Double Strand Breaks Repair Metabolism Laboratory at the Crick.

“For some reason, stem cells have evolved this distinct mechanism of protecting their chromosomes ends, that differs from somatic cells. Why they have, we have no idea, but it’s intriguing. It opens up many questions that will keep us busy for many years to come.”

The team have also helped to clarify years of uncertainty about whether the t-loops themselves play a part in protecting the chromosome ends. They found that telomeres in stem cells with t-loops but without TRF2 are still protected, suggesting the t-loop structure itself has a protective role.

“Rather than totally contradicting years of telomere research, our study refines it in a very unique way. Basically, we’ve shown that stem cells protect their chromosome ends differently to what we previously thought, but this still requires a t-loop,” says Simon Boulton, paper author and group leader in the DNA Double Strand Breaks Repair Metabolism Laboratory at the Crick.

“A better understanding of how telomeres work, and how they protect the ends of chromosomes could offer crucial insights into the underlying processes that lead to premature aging and cancer.”

The team worked in collaboration with Tony Cesare in Sydney and other researchers across the Crick, including Kathy Niakan, of the Human Embryo and Stem Cell Laboratory, and James Briscoe, of the Developmental Dynamics Laboratory at the Crick. “This is a prime example of what the Crick was set up to promote. We’ve been able to really benefit from our collaborator’s expertise and the access that was made possible by the Crick’s unique facilities,” says Simon.

The researchers will continue this work, aiming to understand in detail the mechanisms of telomere protection in somatic and embryonic cells.

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Drug guides stem cells to desired location, improving their ability to heal — ScienceDaily

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Scientists at Sanford Burnham Prebys Medical Discovery Institute have created a drug that can lure stem cells to damaged tissue and improve treatment efficacy — a scientific first and major advance for the field of regenerative medicine. The discovery, published in the Proceedings of the National Academy of Sciences (PNAS), could improve current stem cell therapies designed to treat such neurological disorders as spinal cord injury, stroke, amyotrophic lateral sclerosis?(ALS) and other neurodegenerative disorders; and expand their use to new conditions, such as heart disease or arthritis.

Toxic cells (green) disappeared when mice with a neurodegenerative condition received both therapeutic stem cells (red) and the drug SDV1a-which corresponded with longer lives and delayed symptom onset. These results suggest that SDV1a can be used to improve the efficacy of stem cell treatments.

“The ability to instruct a stem cell where to go in the body or to a particular region of a given organ is the Holy Grail for regenerative medicine,” says Evan Y. Snyder, M.D. Ph.D., professor and director of the Center for Stem Cells & Regenerative Medicine at Sanford Burnham Prebys and senior author of the study. “Now, for the first time ever, we can direct a stem cell to a desired location and focus its therapeutic impact.”

Nearly 15 years ago, Snyder and his team discovered that stem cells are drawn to inflammation — a biological “fire alarm” that signals damage has occurred. However, using inflammation as a therapeutic lure isn’t feasible because an inflammatory environment can be harmful to the body. Thus, scientists have been on the hunt for tools to help stem cells migrate — or “home” — to desired places in the body. This tool would be helpful for disorders in which initial inflammatory signals fade over time — such as chronic spinal cord injury or stroke — and conditions where the role of inflammation is not clearly understood, such as heart disease.

“Thanks to decades of investment in stem cell science, we are making tremendous progress in our understanding of how these cells work and how they can be harnessed to help reverse injury or disease,” says Maria T. Millan, M.D., president and CEO of the California Institute for Regenerative Medicine (CIRM), which partially funded the research. “Dr. Snyder’s group has identified a drug that could boost the ability of neural stem cells to home to sites of injury and initiate repair. This candidate could help speed the development of stem cell treatments for conditions such as spinal cord injury and Alzheimer’s disease.”

A drug with only the “good bits”

In the study, the scientists modified CXCL12 — an inflammatory molecule which Snyder’s team previously discovered could guide healing stem cells to sites in need of repair — to create a drug called SDV1a. The new drug works by enhancing stem cell binding and minimizing inflammatory signaling — and can be injected anywhere to lure stem cells to a specific location without causing inflammation.

“Since inflammation can be dangerous, we modified CXCL12 by stripping away the risky bit and maximizing the good bit,” says Snyder. “Now we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation.”

To demonstrate that the new drug is able to improve the efficacy of a stem cell treatment, the researchers implanted SDV1a and human neural stem cells into the brains of mice with a neurodegenerative disease called Sandhoff disease. This experiment showed SDV1a helped the human neural stem cells migrate and perform healing functions, which included extending lifespan, delaying symptom onset, and preserving motor function for much longer than the mice that didn’t receive the drug. Importantly, inflammation was not activated, and the stem cells were able to suppress any pre-existing inflammation.

Next steps

The researchers have already begun testing SDV1a’s ability to improve stem cell therapy in a mouse model of ALS, also known as Lou Gehrig’s disease, which is caused by progressive loss of motor neurons in the brain. Previous studies conducted by Snyder’s team indicated that broadening the spread of neural stem cells helps more motor neurons survive — so the scientists are hopeful that strategic placement of SDV1a will expand the terrain covered by neuroprotective stem cells and help slow the onset and progressive of the disease.

“We are optimistic that this drug’s mechanism of action may potentially benefit a variety of neurodegenerative disorders, as well as non-neurological conditions such as heart disease, arthritis and even brain cancer,” says Snyder. “Interestingly, because CXCL12 and its receptor are implicated in the cytokine storm that characterizes severe COVID-19, some of our insights into how to selectively inhibit inflammation without suppressing other normal processes may be useful in that arena as well.”

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News

Boosting stem cell activity can enhance immunotherapy benefits — ScienceDaily

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Immune-system T cells have been reprogrammed into regenerative stem cell-like memory (TSCM) cells that are long-lived, highly active “super immune cells” with strong antitumor activity, according to new research from Georgetown Lombardi Comprehensive Cancer Center.

The reprogramming involves a novel approach the researchers developed that inhibits the activity of proteins known as MEK1/2. Currently, several MEK inhibitors are used to effectively treat melanoma, but this study demonstrates that MEK inhibitors don’t just target certain types of cancer cells, but rather, more broadly, reprogram T cells to fight many types of cancer.

The finding appears November 23, 2020, in Nature Immunology.

“Although immunotherapies have improved survival for cancer patients over recent years, survival rates remain sub-optimal. Therefore, there is an urgent need to develop novel, more effective anti-cancer immunotherapies,” says Samir N. Khleif, MD, director of The Jeannie and Tony Loop Immuno-Oncology Laboratory and head of the team that conducted this research. “Our research shows that using drugs that have already been approved for human use may significantly enhance currently available immune therapeutic approaches, thereby leading to better and more durable anti-cancer responses.”

The researchers performed experiments with human cells in the lab and then confirmed the effects of such an approach in mice. The investigators were able to not only identify a novel strategy to reprogram T cells into TSCM cells by using MEK1/2 inhibition, they were able to identify a novel molecular mechanism by which the TSCMs were induced.

The scientists found that reprograming T cells into TSCM can significantly improve T cell therapies for cancer patients. T cell therapy is a process that is widely used in specific cancers and in clinical trials, where immune-system T cells are separated out from a patient’s blood, engineered and expanded with special tumor-targeting capabilities and infused back into the patient to fight cancer. In their experiments, human T cells were reprogrammed with MEK inhibitors into TSCM; additionally, when treating mice with MEK inhibitors, the reprogramming of T cells was also found to induce effective TSCMs.

“Stem cell research has played a vital role this century in enhancing the progress against many diseases. Recent public and private support for stem cell therapy is very gratifying,” says Khleif. “Having stem cell research-specific funding from both governmental and private funders will greatly help accelerate the development of this under-utilized area of research.”

Now that MEK inhibitors have been shown to enhance an anti-tumor immune response, the researchers are starting to look into designing clinical trials to test their research approach in cancer patients. “Our approach is quite novel and we’re anxious to see it put to use in the clinical arena as soon as possible,” concludes Khleif.

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Materials provided by Georgetown University Medical Center. Note: Content may be edited for style and length.

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