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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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CRISPR corrects genetic defect so cells can normalize blood sugar — ScienceDaily

Using induced pluripotent stem cells produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used the gene-editing tool CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured the unrelenting diabetes in those mice.

The findings, from researchers at Washington University School of Medicine in St. Louis, suggest the CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation, and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

The study is published online April 22 in the journal Science Translational Medicine.

Patients with Wolfram syndrome develop diabetes during childhood or adolescence and quickly require insulin-replacement therapy, requiring insulin injections multiple times each day. Most go on to develop problems with vision and balance, as well as other issues, and in many patients, the syndrome contributes to an early death.

“This is the first time CRISPR has been used to fix a patient’s diabetes-causing genetic defect and successfully reverse diabetes,” said co-senior investigator Jeffrey R. Millman, PhD, an assistant professor of medicine and of biomedical engineering at Washington University. “For this study, we used cells from a patient with Wolfram syndrome because, conceptually, we knew it would be easier to correct a defect caused by a single gene. But we see this as a stepping stone toward applying gene therapy to a broader population of patients with diabetes.”

Wolfram syndrome is caused by mutations to a single gene, providing the researchers an opportunity to determine whether combining stem cell technology with CRISPR to correct the genetic error also might correct the diabetes caused by the mutation.

A few years ago, Millman and his colleagues discovered how to convert human stem cells into pancreatic beta cells. When such cells encounter blood sugar, they secrete insulin. Recently, those same researchers developed a new technique to more efficiently convert human stem cells into beta cells that are considerably better at controlling blood sugar.

In this study, they took the additional steps of deriving these cells from patients and using the CRISPR-Cas9 gene-editing tool on those cells to correct a mutation to the gene that causes Wolfram syndrome (WFS1). Then, the researchers compared the gene-edited cells to insulin-secreting beta cells from the same batch of stem cells that had not undergone editing with CRISPR.

In the test tube and in mice with a severe form of diabetes, the newly grown beta cells that were edited with CRISPR more efficiently secreted insulin in response to glucose. Diabetes disappeared quickly in mice with the CRISPR-edited cells implanted beneath the skin, and the animals’ blood sugar levels remained in normal range for the entire six months they were monitored. Animals receiving unedited beta cells remained diabetic. Their newly implanted beta cells could produce insulin, just not enough to reverse their diabetes.

“We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation,” said co-senior investigator Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine and a professor of pathology and immunology. “It’s a proof of concept demonstrating that correcting gene defects that cause or contribute to diabetes — in this case, in the Wolfram syndrome gene — we can make beta cells that more effectively control blood sugar. It’s also possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.”

In the future, using CRISPR to correct certain mutations in beta cells may help patients whose diabetes is the result of multiple genetic and environmental factors, such as type 1, caused by an autoimmune process that destroys beta cells, and type 2, which is closely linked to obesity and a systemic process called insulin resistance.

“We’re excited about the fact that we were able to combine these two technologies — growing beta cells from induced pluripotent stem cells and using CRISPR to correct genetic defects,” Millman said. “In fact, we found that corrected beta cells were indistinguishable from beta cells made from the stem cells of healthy people without diabetes.”

Moving forward, the process of making beta cells from stem cells should get easier, the researchers said. For example, the scientists have developed less intrusive methods, making induced pluripotent stem cells from blood — and they are working on developing stem cells from urine samples.

“In the future,” Urano said, “we may be able to take a few milliliters of urine from a patient, make stem cells that we then can grow into beta cells, correct mutations in those cells with CRISPR, transplant them back into the patient, and cure their diabetes in our clinic. Genetic testing in patients with diabetes will guide us to identify genes that should be corrected, which will lead to a personalized regenerative gene therapy.”

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Review assesses stem cell therapy potential for treating preeclampsia — ScienceDaily

Preeclampsia is the leading cause of death and disability, for both mothers and babies, killing approximately 76,000 mothers and 500,000 babies globally every year. Despite this, the only cure at present is to deliver the placenta and the baby, with the potential for long term complications.

In recent years stem cell therapies have been investigated in animal models. A review article published in Current Hypertension Reports investigates mesenchymal stem/stromal cells (MSCs) as a potential new treatment for preeclampsia.

Senior author, Dr Lana McClements, from the University of Technology Sydney (UTS) said that preeclampsia is a pregnancy complication which manifests as a sudden onset of high blood pressure and organ damage, often involving kidneys or liver, in the second half of pregnancy.

“Most of the deaths associated with preeclampsia occur in developing or low-resource countries however preeclampsia rates in developing countries are increasing due to increase rates of obesity, diabetes and age of women getting pregnant. While there are fewer deaths caused by preeclampsia in developing countries, the economic burden on the healthcare systems is significant,” she says.

“In addition, studies show that beyond life-threatening complications in pregnancy preeclampsia is associated with increased maternal and offspring ill health in later life which makes this review important. If stem cell therapies have potential to treat this condition in pregnancy then their application needs to be assessed for clinical trials,” she says.

Dr McClements and her co-authors from the Mayo Clinic (USA); University of Belgrade (Serbia); University of Nis (Serbia), Queen’s University Belfast (UK) and Serbian Academy of Sciences and Arts, reviewed the therapeutic potential and mechanisms of MSCs in the context of preeclampsia.

MSCs are the most widely used stem cells for treatment of many diseases including cardiovascular disease. More recently, a limited number of studies (five) have tested these stem cells, or their associated secreted cargo (vesicles) as novel treatment options for preeclampsia in pre-clinical (animal) models showing promising results.

The authors say that of particular interest to low-resourced countries are vesicles secreted from these stem cells due to their stability and avoiding the need for expensive GMP cell manufacturing facilities.

“Preeclampsia develops due to a complex set of conditions. Our review shows that there is potential to use stem cells as therapy but we still don’t understand the mechanism by which MSCs might repair damage in the condition.

“Further work is needed to maximize their therapeutic potential and minimise possible side effects before they can be introduced in a clinical setting, this is why we are pursuing this important research in my laboratory at UTS to help treat such a devastating disease,” Dr McClements says.

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

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Researchers repurpose classic chemotherapy drug to overcome cancer therapy resistance — ScienceDaily

Drug resistance is a major obstacle in cancer treatment — leading to relapse for many patients. In a new study, published online April 20, 2020, in Nature Cell Biology, researchers from the Stowers Institute for Medical Research, Children’s Mercy Kansas City, and The University of Kansas Cancer Center report on a promising new strategy to overcome drug resistance in leukemia, using targeted doses of the widely-used chemotherapy drug doxorubicin.

The study’s researchers found that low doses of the anthracycline antibiotic doxorubicin inhibit the interaction between two molecular pathways that work closely together to promote tumor growth and resistance to therapy. The targeted approach also clears the way for cancer-targeting immune cells to do their work, an unexpected and novel finding, according to the study authors.

“In low doses, doxorubicin actually stimulated the immune system, in contrast with the typical clinical doses, which were immunosuppressive, killing healthy immune cells indiscriminately,” says John M. Perry, PhD, a researcher with the Children’s Mercy Research Institute at Children’s Mercy. He completed his postdoctoral work at Stowers and is first author of the report.

The findings are the result of a decade-spanning collaborative effort among researchers at the Stowers Institute, Children’s Mercy, The University of Kansas Cancer Center and other institutions, evolving from their studies on how normal, healthy stem cells self-renew.

Early in their studies, Stowers Institute Investigator Linheng Li, PhD, and Research Specialist Xi He, MD, showed that the protein kinase Akt could enhance Wnt signaling via phosphorylating beta-catenin, thus promoting tumorigenesis in the gut. Perry further investigated the Wnt/beta-catenin and PI3K/Akt pathways in the hematopoietic (blood-forming) system. Using a mouse model with genetic modifications of the Wnt/beta-catenin and PI3K/Akt pathways, Perry found that the two pathways cooperate to drive stem cell renewal, thus resulting in excessive blood-forming stem cell production. But instead of just expanding the stem cells, the permanent activation of the pathways caused the mice also to develop leukemia. Intrigued, the researchers shifted their focus to inhibiting interaction between those same pathways to target leukemia stem cells.

Many drugs that directly target the Wnt/beta-catenin or PI3K/Akt pathways eventually fail because cancer cells evolve resistance to them, and broadly-acting chemotherapeutic drugs can have harsh side effects and systemic toxicity. The researchers collaborated with Scott Weir, PhD, and Anuradha Roy, PhD, at The University of Kansas (KU) Cancer Center, to search for an alternative among the compounds cataloged in the center’s small molecule library.

“Our idea was to find a drug with the goal of blocking the interaction between Wnt/beta-catenin and PI3K/Akt and reduce the toxicity,” says Li, who serves as liaison between Stowers and the KU Cancer Center and co-leads the center’s cancer biology research program.

The team conducted high-throughput drug screening, which showed that doxorubicin did the best job of inhibiting the interaction between the two pathways. They found that the drug’s inhibitory powers worked at low doses, which offers an advantage over administering it at high doses as a chemotherapeutic drug where it can cause lasting heart damage in some patients.

Samples collected from pediatric leukemia patients at Children’s Mercy were also central to the study. A diagnostic sample was collected from each patient before and after chemotherapy treatment to compare therapy-resistant leukemia stem cells to therapy-sensitive leukemia stem cells. Then the samples were transplanted into mice to test whether they developed leukemia and whether low-dose doxorubicin treatment improved their survival and reduced leukemia development.

“We found that mice receiving patient sample transplants with therapy-resistant leukemia stem cells rapidly developed leukemia, but low-dose doxorubicin treatment improved survival by reducing leukemia stem cells,” Perry says. “However, mice receiving patient sample transplants that did not contain therapy-resistant leukemia stem cells did not respond to low-dose doxorubicin treatment. These results showed that chemoresistant leukemia stem cells from patients could be functionally reduced with low-dose doxorubicin treatment, at least in an in vivo animal model assay.”

After successful testing in mouse models, the researchers worked with Tara Lin, MD, at the KU Cancer Center to conduct a small-scale clinical trial to test low-dose anthracycline treatment on adults with treatment-resistant acute myeloid leukemia (AML). The trial used daunorubicin, a chemotherapy drug in the same class as doxorubicin, which is widely used in treating AML. Bone marrow was collected immediately prior to treatment and again post-treatment. Half of the study participants responded to the treatment and had reduced numbers of leukemia stem cells exhibiting the Akt-activated beta-catenin biomarker.

In addition to these encouraging results, the overarching study also revealed surprising insights into immune escape — a hallmark of cancer development in which cancerous cells evade the immune system and proliferate. Mechanistically, they found that leukemia stem cells express multiple proteins known as immune checkpoints, which turn off immune responses that might otherwise recognize and eliminate leukemia stem cells. Another team member, Fang Tao, PhD, uncovered that beta-catenin binds to multiple immune checkpoint gene loci. Low-dose doxorubicin treatment reduced expression of these immune checkpoints, including PD-L1, TIM3, and CD24, which exposed otherwise resistant leukemia stem cells to immune-mediated cell killing.

Going forward, at Children’s Mercy, Perry is conducting further research to understand ways to screen other drugs that synergize with low-dose doxorubicin to kill resistant cells while reactivating anticancer immunity in pediatric patients. His team has recently launched a clinical trial on low-dose doxorubicin in pediatric patients. At Stowers, the Li Lab is investigating similar strategies for overcoming cancer therapy resistance in solid tumor cancers including breast cancer, glioblastoma, and colon cancer.

“The research holds promise as a more effective strategy to overcome cancer therapy resistance and immune escape that can be used in combination with other cancer therapies including chemotherapy, radiation, and immunotherapy for patients with leukemia and other types of cancer,” Li says.

Low-dose doxorubicin also avoids the harsh side effects of high-dose doxorubicin, potentially offering patients a better quality of life. In high doses, doxorubicin damages the heart muscle. Even when patients survive long-term, highly toxic anticancer treatments often cause long-term health problems and reduced life expectancy.

“Pediatric patients should live another half-century or more, so we need to do a better job of ensuring not only long-term survival, but healthy and productive lives,” Perry says.

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Stem cells in human embryos commit to specialization surprisingly early — ScienceDaily

The point when human embryonic stem cells irreversibly commit to becoming specialised has been identified by researchers at the Francis Crick Institute.

Our biological history can be traced back to a small group of cells called embryonic stem cells, which through cell division, give rise to cells that specialise to perform a specific role in the body — a process known as differentiation.

Understanding when and how embryonic stem cells specialise provides insights into healthy differentiation and how cells ‘remember’ what type of cell they are. This process can go wrong in cancer, when cells ‘forget’ their identity and change into the wrong type.

As part of the research, published in Cell Stem Cell, Crick scientists found that embryonic stem cells differentiate unexpectedly early, irreversibly committing to become each of the more than 200 cell types in the body.

They showed this was as a result of a newly identified small group of genes becoming activated, which they named ‘early-commitment genes’.

“Working with stem cells and mathematical models, we’ve identified a new class of genes which are responsible for regulating one of the earliest stages of human development,” says Silvia Santos, author and group leader in the Quantitative Cell Biology Laboratory at the Crick.

“Once these genes are activated, it’s a question of minutes before the cells fully commit to differentiation. The speed of this is incredibly surprising, especially if you consider how the first signs of differentiation, that’s the embryo developing the first embryonic germ layers, take about three days. These layers ultimately give rise to all the tissues in the growing fetus weeks later.”

The researchers focused on one early-commitment gene, called GATA3. When this gene was activated experimentally in the lab, embryonic stem cells quickly committed to differentiation. On the other hand, when this gene was deleted, this process was sluggish and not quite right.

“GATA3 is crucial to the healthy, timely differentiation of stem cells. Once it’s switched on, this gene triggers a positive feedback loop, which helps it stay active. In turn, this ensures that the cells remain differentiated, and do not reverse back to a stem cell state,” says Alexandra Gunne-Braden, co-lead author and postdoc in the Quantitative Cell Biology Laboratory at the Crick.

This research used stem cells taken from embryos donated by people undergoing IVF. The donated embryos were not needed in the course of their fertility treatment and would have otherwise been destroyed.

“When embryonic stem cells commit to specialisation is a fundamental and yet until now, unanswered question,” continues Silvia Santos.

“It’s important we understand more about this, as the healthy function of cells is underpinned by the process of how cells acquire and remember their identity during the process of differentiation. This valuable insight into early human development could open up new avenues for research into diseases that occur when this process goes wrong.”

Story Source:

Materials provided by The Francis Crick Institute. Note: Content may be edited for style and length.

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