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Model of the early embryonic brain — ScienceDaily

We know a lot about the human brain, but very little about how it is formed. In particular, the stages from the second to the seventh week of embryonic development have so far been virtually unknown territory to brain researchers.

To learn more about this particular period, researchers from the Department of Neuroscience and the Novo Nordisk Foundation Center for Stem Cell Biology at the Faculty of Health and Medical Sciences have now developed a model that mimics these early stages of the human brain in the laboratory.

The model is based on embryonic stem cells grown in a microfluidic system developed in collaboration with bioengineers from Lund University in Sweden.

‘We know that in the early embryonic stage the brain is exposed to various concentrations of growth factors which induces the formation of different brain regions. By using microfluidic methods, we can — under extremely controlled conditions — recreate the environment found in the early embryo, explains the first author on the study, Assistant Professor Pedro Rifes.

‘When we expose stem cells to the controlled environment, we can create a tissue that resembles an embryonic brain at a very early stage, about 4-5 weeks after fertilisation of the egg — a stage that we have so far not been able to study’.

The Developmental Tree of the Human Brain

The researchers will use the new model to make a map of the development of the brain cells — a kind of ‘Developmental tree’ of the brain, thereby learning new things about how the enormous complexity of different nerve cells in the human brain is formed during the early embryonic stages.´

‘For the first time, we have access to a tissue that resembles the early embryonic brain, and this allows us togo in and analyse what happens to each individual cell at each stage of development’, says the principal scientist behind the study, Associate Professor Agnete Kirkeby.

The idea is that brain researchers around the world will be able to use this ‘Developmental tree’ of the brain as a guide to produce different types of nerve cells for stem cell therapy. By studying the natural development of the nerve cells, the researchers will be able to speed up the creation of recipes for producing specific nerve cells in the laboratory.

A Recipe for Stem Cell Treatment

Agnete Kirkeby is well aware of the importance of a faster path to stem cell treatments. Together with colleagues from Lund and Cambridge, she has for several years worked on developing a stem cell therapy for Parkinson’s disease. This project required Kirkeby and her colleagues to produce a very specific type of nerve cells, the dopaminergic nerve cells, which are the cells that are lost in Parkinson’s Disease.

‘We have come a long way in the project and will soon be able to test the stem cell treatment in humans for the first time. But it took us more than 10 years to get this far because we depended on a trial-and-error methodology to develop the right nerve cells from the stem cells’.

With knowledge from the new model, the researchers expect to be able to considerably shorten this process in the future.

‘If we understand exactly how the brain develops in the early stages, we will become better at guiding the stem cells in the right direction when producing human nerve cells in the lab. This will allow us to more quickly and efficiently develop cell treatments for neurological diseases such as epilepsy, Parkinson’s Disease and certain types of dementia’, says Agnete Kirkeby.

New Options for testing Environmental Toxins

In addition to increasing our knowledge on brain development and easing the path to future stem cell treatments, Agnete Kirkeby believes that the embryonic brain model may serve other useful purposes as well.

‘The model may be used to investigate how brain cells in the early embryonic stages react to certain chemicals surrounding us in our daily lives — these might be substances in our environment, in consumer products or in the medications that some pregnant women may require. So far, we have not had a good model to test precisely this’.

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A new algorithm combines gradient methods with fast Fourier transforms to quantify the organization of cardiac myofibrils — ScienceDaily

Heart disease is the leading cause of death in the United States and other industrialized nations, and many patients face limited treatment options. Fortunately, stem cell biology has enabled researchers to produce large numbers of cardiomyocytes, the cells that make up the heart or cardiac muscle and have the potential to be used in advanced drug screens and cell-based therapies.

One of the pitfalls of these stem cell-generated cardiomyocytes is that they do not represent adult human cardiomyocytes but remain immature without further intervention. Additionally, current image analysis techniques do not allow researchers to analyze heterogeneous, multidirectional, striated myofibrils typical of immature cells to determine when new interventions are coaxing the cells to organize.

In the Journal of Applied Physics, from AIP Publishing, researchers showcase an algorithm that combines gradient methods with fast Fourier transforms, the scanning gradient Fourier transform or SGFT technique, to quantify myofibril structures in heart cells with considerable accuracy. Myofibrils are the elongated contractile unit of a muscle cell.

“If you look at adult human cardiac tissue, everything is not in perfect alignment. Everything is not stacked nicely and neatly like a bookshelf,” said Wendy Crone, an author of the paper. “The structures are more complicated. We wanted to be able to quantify the organization.”

This level of analysis, combined with new emerging studies of the effects of cell mutation, has the potential to produce new insights regarding the mechanisms underlying the generation of myofibrils and various cardiomyopathies, which make it harder for the heart muscle to pump blood to the rest of the body.

“There is myofibril disarray in certain diseases of the heart,” said Crone. “With our technique, we can quantify the disarray, which provides a better understanding of the severity of disease in heart cells.”

The heterogeneous, striated patterning that this new method can detect and quantify occurs in countless other instances in biology and elsewhere. For instance, the SGFT technique clearly detects the distribution of collagen organization and orientation in breast tissue biopsies, which is significant since breast tissue with cancer has more organized collagen structures. As prior studies have shown, the morphology of collagen fibers in breast cancer tissue is a strong prognostic indicator of the malignancy of the tumor.

The SGFT technique could also potentially be used to quantify striated patterns in early stage neurons derived from stems cells.

“Our code can quantify the organization of neural rosettes, too,” said Crone.

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Materials provided by American Institute of Physics. Note: Content may be edited for style and length.

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New research into stem cell mutations could improve regenerative medicine — ScienceDaily

Research from the University of Sheffield has given new insight into the cause of mutations in pluripotent stem cells and potential ways of stopping these mutations from occurring.

The findings, published in Stem Cell Reports, show that pluripotent stem cells are particularly susceptible to DNA damage and mutations compared to other cells, and this could cause genetic mutations.

Pluripotent stem cells are able to develop into any cell type in the body, and there is considerable interest in using them to produce cells to replace diseased or damaged tissues in applications referred to as regenerative medicine.

One concern for the safety of this is that these cells often acquire recurrent mutations which might lead to safety issues if used in patients.

The researchers have found that these mutations are more likely to occur in a certain point during their cell cycle and have suggested ways of growing the cells to dramatically reduce the susceptibility to DNA damage and potentially the mutations that arise.

Peter Andrews, Professor of Biomedical Science at the University of Sheffield, said: “Clinical trials of regenerative medicine using cells derived from pluripotent stem cells are now beginning around the world, but there are concerns that mutations in the pluripotent stem cells may risk patient safety. Our results may allow us to significantly reduce that risk.

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

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Findings could lead to better methods for creating muscle cells from stem cells — ScienceDaily

An interdisciplinary team of researchers at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA has developed a first-of-its-kind roadmap of how human skeletal muscle develops, including the formation of muscle stem cells.

The study, published in the peer-reviewed journal Cell Stem Cell, identified various cell types present in skeletal muscle tissues, from early embryonic development all the way to adulthood. Focusing on muscle progenitor cells, which contribute to muscle formation before birth, and muscle stem cells, which contribute to muscle formation after birth and to regeneration from injury throughout life, the group mapped out how the cells’ gene networks — which genes are active and inactive — change as the cells mature.

The roadmap is critical for researchers who aim to develop muscle stem cells in the lab that can be used in regenerative cell therapies for devastating muscle diseases, including muscular dystrophies, and sarcopenia, the age-related loss of muscle mass and strength.

“Muscle loss due to aging or disease is often the result of dysfunctional muscle stem cells,” said April Pyle, senior author of the paper and a member of the Broad Stem Cell Research Center. “This map identifies the precise gene networks present in muscle progenitor and stem cells across development, which is essential to developing methods to generate these cells in a dish to treat muscle disorders.”

Researchers in Pyle’s lab and others around the world already have the capacity to generate skeletal muscle cells from human pluripotent stem cells — cells that have the ability to self-renew and to develop into any cell type in the body. However, until now, they had no way of determining where these cells fall on the continuum of human development.

“We knew that the muscle cells we were making in the lab were not as functional as the fully matured muscle stem cells found in humans,” said Haibin Xi, first author of the new paper and an assistant project scientist in Pyle’s lab. “So we set out to generate this map as a reference that our lab and others can use to compare the genetic signatures of the cells we are creating to those of real human skeletal muscle tissue.”

To create this resource, the group gathered highly specific data about two different groups of skeletal muscle cells: those from the human body, ranging from the fifth week of embryonic development to middle age, and those derived from human pluripotent stem cells the researchers generated in the lab. They then compared the genetic signatures of cells from both sources.

The group obtained 21 samples of human skeletal muscle tissue from their UCLA collaborators and from colleagues at the University of Southern California and the University of Tübingen in Germany. For the pluripotent stem cell-derived muscle cells, the group evaluated cells created using their own unique method and the methods of several other groups.

The Pyle lab collaborated with the lab of Kathrin Plath, a UCLA professor of biological chemistry and member of the Broad Stem Cell Research Center, to conduct high-throughput droplet-based single-cell RNA sequencing of all of the samples. This technology enables researchers to identify the gene networks present in a single cell and can process thousands of cells at the same time. Leveraging the power of this technology and the Plath lab’s bioinformatics expertise, the group identified the genetic signatures of various cell types from human tissues and pluripotent stem cells.

They next developed computational methods to focus on muscle progenitor and stem cells and mapped out their gene networks associated with every developmental stage. This enabled the group to match the genetic signatures found in the pluripotent stem cell-derived muscle cells with their corresponding locations on the map of human muscle development.

The group found that pluripotent stem cell-derived muscle cells produced by all the methods they tried resembled muscle progenitor cells at an early developmental state and did not align to adult muscle stem cells.

In addition to pinning down the true maturity of the lab-produced cells, this analysis also provided details about the other cell types present in skeletal muscle tissue across development and in populations derived from human pluripotent stem cells. These cells could play an essential role in muscle cell maturation and could be critical to improving methods to generate and support muscle stem cells in a dish.

“We found that some methods to generate muscle cells in a dish also produce unique cell types that likely support the muscle cells,” said Pyle, who is also a member of the UCLA Jonsson Comprehensive Cancer Center. “And so now our questions are, what are these cells doing? Could they be the key to producing and supporting mature and functional muscle stem cells in a dish?”

Moving forward, Pyle and her colleagues will focus on harnessing this new resource to develop better methods for generating muscle stem cells from human pluripotent stem cells in the lab. She hopes that by focusing on the stem cell-associated gene expression networks and supportive cell types they identified, they can produce high-powered muscle stem cells that can be useful for future regenerative therapies.

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First ‘biomarker’ for regenerative medicine may help researchers identify the people most likely to benefit from stem cell treatment — ScienceDaily

Scientists at Sanford Burnham Prebys Medical Discovery Institute and Loma Linda University Health have demonstrated the promise of applying magnetic resonance imaging (MRI) to predict the efficacy of using human neural stem cells to treat a brain injury — a first-ever “biomarker” for regenerative medicine that could help personalize stem cell treatments for neurological disorders and improve efficacy. The researchers expect to test the findings in a clinical trial evaluating the stem cell therapy in newborns who experience a brain injury during birth called perinatal hypoxic-ischemic brain injury (HII). The study was published in Cell Reports.

“In order for stem cell therapies to benefit patients, we need to be thoughtful and scientific about who receives these treatments,” says Evan Y. Snyder, M.D., Ph.D., professor and director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys, and corresponding study author. “I am hopeful that MRI, which is already used during the course of care for these newborns, will help ensure that infants who experience HII get the best, most appropriate treatment possible. In the future, MRI could help guide the use of stem cells to treat — or in some instances, not treat — additional brain disorders such as spinal cord injury and stroke.”

Scientists now understand that, in many instances, human neural stem cells are therapeutic because they can protect living cells — in contrast to “re-animating” or replacing nerve cells that are already dead. As a result, understanding the health of brain tissue prior to a stem cell transplant is critical to the treatment’s potential success. Tools that help predict the efficacy of neural stem cell therapy could increase the success of clinical trials, which are ongoing in people with Parkinson’s disease, spinal cord injury and additional neurological conditions, while also sparing people who will not respond to treatment from an invasive procedure that offers false hope.

“We know that stem cell therapies hold extraordinary promise, but, like other medicines, they also need to be given at the right time and to the right patients,” says Steve Lin, Ph.D., senior science officer at the California Institute for Regenerative Medicine, which partially funded the research. “This study suggests that a readily available technique, MRI — which is already used in many brain injuries to determine the extent of neurological damage — may be a useful tool to determine who will or will not benefit from neural stem treatment.”

Protecting newborns from brain damage

Snyder, a neonatologist and pediatric neurologist, has long envisioned using human neural stem cells to protect newborns with acute perinatal HII from brain damage. He and his colleagues made the discovery that MRI could be used as an objective, quantifiable, readily available basis for inclusion and exclusion criteria for this treatment while engaged in preclinical studies required prior to starting human clinical trials for babies with HII. This birth injury affects two to four newborns out of every 1,000 babies born in the U.S. and is attributable to a number of complications, including umbilical cord compression, disrupted maternal blood pressure and maternal infection.

“My hope is that human neural stem cells can help rescue enough injured and vulnerable — though not dead — neural cells,” explains Snyder. “This could help prevent the most severely affected infants from developing cerebral palsy, epilepsy, intellectual disability or other neurological disorders that often arise after HII if left untreated.”

In the study, the scientists used MRI to measure two areas surrounding the regions of HII brain injury in rats: the penumbra, a region that consists of mildly injured, “stunned” neurons; and the core, an area that consists of dead neurons. They found that rats with a larger penumbra and smaller core that received human neural stem cells had better neurological outcomes — including improved memory — demonstrated by the ability to swim to a hidden platform (Morris Water Maze test), and a greater willingness to venture into a brightly lit area (open field test).

In these rats, the penumbra — to which the neural stem cells homed avidly — became normal tissue (based on MRI and histological standards), while the core remained unimproved and attracted few cells. Penumbra that did not receive cells became part of the core, populated by dead neurons — indicating the benefit of the stem cell treatment.

“This approach to brain lesion classification is a powerful patient stratification tool that allows us to identify newborns who may benefit from this stem cell therapy — and protect others from undergoing unnecessary treatment,” says Snyder. “Based on our findings, only newborns with a large penumbral volume in relation to core volume should receive a transplant of human neural stem cells. Equally important, newborns so severely injured that only a core is present, or babies with such a mild case of HII that not even a penumbra is present, should not receive human neural stem cells, as the treatment is unlikely to be impactful.”

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Little skates could hold the key to cartilage therapy in humans — ScienceDaily

Nearly a quarter of Americans suffer from arthritis, most commonly due to the wear and tear of the cartilage that protects the joints. As we age, or get injured, we have no way to grow new cartilage. Unlike humans and other mammals, the skeletons of sharks, skates, and rays are made entirely of cartilage and they continue to grow that cartilage throughout adulthood.

And new research published this week in eLife finds that adult skates go one step further than cartilage growth: They can also spontaneously repair injured cartilage. This is the first known example of adult cartilage repair in a research organism. The team also found that newly healed skate cartilage did not form scar tissue.

“Skates and humans use a lot of the same genes to make cartilage. Conceivably, if skates are able to make cartilage as adults, we should be able to also,” says Andrew Gillis, senior author on the study and a Marine Biological Laboratory Whitman Center Scientist from the University of Cambridge, U.K.

The researchers carried out a series of experiments on little skates (Leucoraja erinacea) and found that adult skates have a specialized type of progenitor cell to create new cartilage. They were able to label these cells, trace their descendants, and show that they give rise to new cartilage in an adult skeleton.

Why is this important? There are few therapies for repairing cartilage in humans and those that exist have severe limitations. As humans develop, almost all of our cartilage eventually turns into bone. The stem cell therapies used in cartilage repair face the same issue — the cells often continue to differentiate until they become bone. They do not stop as cartilage. But in skates, the stem cells do not create cartilage as a steppingstone; it is the end result.

“We’re looking at the genetics of how they make cartilage, not as an intermediate point on the way to bone, but as a final product,” says Gillis.

The research is in its early stages, but Gillis and his team hope that by understanding what genes are active in adult skates during cartilage repair, they could better understand how to stop human stem-cell therapies from differentiating to bone.

Note: There is no scientific evidence that “shark cartilage tablets” currently marketed as supplements confer any health benefits, including relief of joint pain.

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Materials provided by Marine Biological Laboratory. Original written by Emily Greenhalgh. Note: Content may be edited for style and length.

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More selective elimination of leukemia stem cells and blood stem cells — ScienceDaily

Acute myeloid leukemia (AML) is an aggressive cancer of the blood-forming system. It affects the hematopoietic stem cells, or blood stem cells, of various white blood cells and of the red blood cells and platelets. The leukemic stem cells propagate quickly, spread in the bone marrow and blood, and can attack other organs. Patients are usually treated with intensive chemotherapy and sometimes radiotherapy. After that they require a transplant of hematopoietic stem cells from a healthy donor. There are serious side effects associated with the treatment and it is therefore unsuitable for many patients.

Selectively eliminating leukemic and hematopoietic stem cells

A team of scientists and physicians from the University of Zurich (UZH), the University Hospital Zurich (USZ) and ETH Zurich have now managed to eliminate the leukemic and hematopoietic stem cells more selectively in an animal model. Chemotherapy and radiotherapy not only destroy the cancerous and hematopoietic stem cells, but affect all dividing cells — i.e. practically all tissues. “Compared to normal strategies, our method works very selectively, meaning that mature blood cells and other tissues are spared,” says study leader Markus Manz, professor of medicine at UZH and director of the Department of Medical Oncology and Hematology at USZ.

The researchers used the novel cell therapy called CAR-T. This therapy uses genetic modification to equip human immune cells with a receptor, thanks to which they can systematically dock onto only the leukemic stem cells and the healthy hematopoietic stem cells and destroy them. This creates space for the new donor cells to be transplanted. To avoid that the genetically modified immune cells then also attack the hematopoietic stem cells from the donor, the CAR-T cells are deactivated after they have done their work and before the transplant. This is done by using an antibody against a surface marker of the CAR-T cells. After the donor stem cell transplant, they take their place in the bone marrow and begin to rebuild the hematopoietic and immune system.

Clinical use of selective immune-mediated elimination planned

The results were achieved using cell cultures in the lab and in mice with human blood and cancer cells. But Markus Manz is confident that the treatment could also be effective in humans: “The principle works: It is possible to eliminate, with high precision, the leukemic and hematopoietic stem cells in a living organism.” Researchers are currently testing whether the method is only possible with CAR-T cells or also with simpler constructs — such as T-cell-activating antibodies. As soon as the pre-clinical work is completed, Manz wants to test the new immunotherapy in a clinical study with humans. “If our method also works with humans, it could replace chemotherapy with its serious side effects, which would be a great benefit for patients with acute myeloid leukemia or other hematopoietic stem cell diseases,” explains Manz.

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

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Accumulation of gene mutations in chronic Graft-versus-host disease — ScienceDaily

Mutations in white blood cells can contribute to abnormal immune profile after hematopoietic stem cell transplantation.

Graft-versus-host disease (GvHD) is a potentially life-threatening medical condition that is common after allogeneic hematopoietic stem cell transplantation, the only curative treatment for various types of leukemias. In GvHD, white blood cells from transplant donor recognize recipient cells as non-self and attack recipient tissues. Understanding how these donor white blood cells remain active against recipient cells can pave the way for novel treatment strategies in GvHD.

A research project led by Professor Satu Mustjoki at the University of Helsinki investigated the role of T cell mutations in GvHD. Somatic or so-called acquired mutations during lifetime are common in cancer cells, but little is known about their existence and significance in other cells, such as cells in the body’s defense system.

Published in the journal Nature Communications, the study first identified an index chronic GvHD patient with an activating somatic mutation in a gene called mTOR, which regulates cell growth and cell survival.

The authors then screened an international cohort of 135 GvHD patients and 54 healthy blood donors. By using next generation sequencing, the scientists found that 2.2% of chronic GvHD patients, but none of the healthy blood donors, harbored a mutation in mTOR.

“What makes our finding particularly significant is that the mutation now found was recurrent, meaning that the same mutation was found in several patients with chronic GvHD,” says professor Satu Mustjoki.

“Our previous studies in rheumatoid arthritis had shown that acquired mutations could be found in T cells, but in these studies, the mutations had been isolated and the same mutations had not been found in more than one patient.”

Individualized treatments for patients

Using single-cell RNA sequencing and T cell receptor sequencing on samples collected from the index patient, researchers found that the mTOR mutated CD4+ T cell clone expanded during the course of GvHD despite immunosuppressive treatment, suggesting the mutation contributed to the disease pathogenesis.

In addition, it was found that the mutation was located in so-called cytotoxic T cells and these cells were able to damage the body’s own cells. Researchers also investigated the mTOR mutation in more detail by introducing it into a human cell line. The activating mTOR mutation promoted cell proliferation and cell survival.

The researchers performed a high-throughput drug screen with 527 drugs to identify potential targeted therapies. The index patients’ CD4+ T cells were sensitive to a specific class of drugs called HSP90 inhibitors, suggesting that these drugs could be used to treat GvHD in the future.

“Our study helps to understand the mechanisms of activation of the immune system in GvHD. Although several different drug combinations have been tried in the treatment of GvHD, using our results, it is possible to find individualized treatments for patients,” says doctoral candidate Daehong Kim from the University of Helsinki.

Further studies using larger cohorts of GvHD are warranted to understand whether clonal mutations in T cells modify GvHD severity, drug responses and clinical outcome.

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Materials provided by University of Helsinki. Original written by Miia Soininen. Note: Content may be edited for style and length.

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Cellular mechanism involved in Krabbe disease — ScienceDaily

A group of researchers at the University at Buffalo have published a paper that clarifies certain cellular mechanisms that could lead to improved outcomes in patients with globoid cell leukodystrophy, commonly known as Krabbe disease.

The paper, titled “Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction,” was published today (May 5) in the journal Neuron.

The research was led by Lawrence Wrabetz, MD, and M. Laura Feltri, MD. Wrabetz and Feltri head the Hunter James Kelly Research Institute and both are professors in the departments of Biochemistry and Neurology in the Jacobs School of Medicine and Biomedical Sciences at UB.

The institute is named for the son of former Buffalo Bills quarterback Jim Kelly. Hunter Kelly died at age 8 in 2005 from complications of Krabbe disease.

Krabbe disease is a progressive and fatal neurologic disorder that usually affects newborns and causes death before a child reaches the age of 2 or 3.

Traditionally, hematopoietic stem cell transplantation, also known as a bone marrow transplant, has improved the long-term survival and quality of life of patients with Krabbe disease, but it is not a cure.

It has long been assumed that the bone marrow transplant works by a process called cross-correction, in which an enzyme called GALC is transferred from healthy cells to sick cells.

Using a new Krabbe disease animal model and patient samples, the UB researchers determined that in reality cross-correction does not occur. Rather, the bone marrow transplant helps patients through a different mechanism.

The researchers first determined which cells are involved in Krabbe disease and by which mechanism. They discovered that both myelin-forming cells, or Schwann cells, and macrophages require the GALC enzyme, which is missing in Krabbe patients due to genetic mutation.

Schwann cells require GALC to prevent the formation of a toxic lipid called psychosine, which causes myelin destruction and damage to neurons. Macrophages require GALC to aid with the degradation of myelin debris produced by the disease.

The research showed that hematopoietic stem cell transplantation does not work by cross-correction, but by providing healthy macrophages with GALC.

According to Feltri, the data reveal that improving cross-correction would be a way to make bone marrow transplants and other experimental therapies such as gene therapy more effective.

“Bone marrow transplantation and other treatments for lysosomal storage disorders, such as enzyme replacement therapy, have historically had encouraging but limited therapeutic benefit,” said study first author Nadav I. Weinstock, an MD-PhD student in the Jacobs School. “Our work defined the precise cellular and mechanistic benefit of bone marrow transplantation in Krabbe disease, while also shedding light on previously unrecognized limitations of this approach.

“Future studies, using genetically engineered bone marrow transplantation or other novel approaches, may one day build on our findings and eventually bridge the gap for effectively treating patients with lysosomal disease,” he continued.

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Materials provided by University at Buffalo. Original written by Barbara Branning. Note: Content may be edited for style and length.

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Potential for cell replacement therapy — ScienceDaily

The loss of insulin-secreting beta cells by autoimmune destruction leads to type 1 diabetes. Clinical islet cell transplantation has the potential to cure diabetes, but donor pancreases are rare. In a new study, a group of researchers developed an improved pluripotent stem cell differentiation protocol to generate beta cells in vitro with superior glucose response and insulin secretion. This is a major step towards beta cell replacement therapy.

Human pluripotent stem cells (either human embryonic stem cells or induced pluripotent stem cells) can differentiate into every cell type of the human body with unlimited self-renewing capacity. Hence, pluripotent stem cells are an optimal source to generate specialized cell types for cell replacement therapy, e.g. beta cells for diabetic patients. However, current in vitro beta cell differentiation protocols are very complex due to the high number of differentiation steps. The process requires almost 20 signaling proteins and small molecules to regulate the growth and differentiation of the cells and lasts for more than four weeks. Within this multi-step process not all cells differentiate into the targeted cells but take wrong differentiation paths. This can lead to a highly heterogeneous cell population with beta cells which are not completely functional. A group of researchers at Helmholtz Zentrum München, the German Center for Diabetes Research (DZD), Technical University of Munich (TUM) and Miltenyi Biotec therefore tried to improve the quality of stem cell-derived beta cells.

CD177 quality control

The researchers developed an approach to enrich the stem cell culture with highly specialized pancreas progenitors which might lead to a more targeted differentiation into beta cells. “From developmental biology we knew that pancreatic progenitors are already specified at the endoderm stage — the first step of differentiation. We needed to find out if this was true also for human pluripotent stem cell differentiation,” explains Prof. Heiko Lickert, Director at the Institute of Diabetes and Regeneration Research at Helmholtz Zentrum München, Professor of Beta Cell Biology at TUM School of Medicine and member of the Research Coordination Board of the German Center for Diabetes Research (DZD).

To investigate on this, the researchers were looking for a possibility to better control the quality of the endoderm and its differentiation into specified pancreas progenitors. In a cooperation with Sebastian Knöbel’s group at Miltenyi Biotec they identified a monoclonal antibody called CD177 which marks a subpopulation of the endoderm that efficiently and homogenously differentiates into specified pancreatic progenitors. CD177 can therefore function as a quality control. “With CD177 we can already see at an early stage if the cells are on the right differentiation track. This can help save lots of time, efforts and money,” says Lickert.

Enriching the stem cell culture with CD177 at the endoderm stage increases the generation of specified pancreatic progenitors. Ultimately, this leads to more mature and more functional beta cells that respond better to glucose and show improved insulin secretion patterns.

Cell replacement therapy, disease modelling and drug screening

Current beta cell differentiation protocols generate very heterogeneous cell populations that not only contain beta cells, but also remaining pancreatic progenitors or cell types from a different lineage. The purification by CD177 will not only improve the homogeneity and quality of the generated beta cells but also increase their clinical safety, as pluripotent stem cells are separated out. This is a crucial step towards the clinical translation of stem cell-derived beta cell replacement therapy for patients with type 1 diabetes.

Furthermore, as CD177 generated beta cells are more similar to beta cells in the human body, the CD177 protocol will help to establish disease modeling systems that can mimic the human pancreas. In addition, a differentiation protocol giving rise to functional beta cells is of highest interest for drug screening approaches.

About this study

This study was a collaboration between Helmholtz Zentrum München, the German Center for Diabetes Research (DZD), Technical University of Munich (TUM) and Miltenyi Biotec. It was funded by the German Center for Diabetes Research (DZD), the EU consortium HumEN (“Up-scaling human insulin-producing beta cell production by efficient differentiation and expansion of pancreatic endoderm progenitors” — HEALTH.2013.1.4-1. Controlling differentiation and proliferation in human stem cells intended for therapeutic use. FP7-HEALTH-2013-INNOVATION-1) and the European Union’s Horizon 2020 research and innovation program under grant agreement number 874839.

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