TAG: "Stem cells"

Tracing the beginnings of hematopoietic stem cells


Researchers uncover clues to development of cells that produce all adult blood cells.

Scanning electron micrograph of a red blood cell, a platelet and a white blood cell

Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the UC San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells.

Principal investigator David Traver, Ph.D., professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. “Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” said Traver. “What has not been known is where, when and how Notch signal transduction is mediated.”

Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite – embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues – much earlier in the process than previously anticipated.

More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.

“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” said Traver. “This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”

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Clinical trial will evaluate safety of stem cell transplantation in spine


UC San Diego is recruiting patients for the study.

Researchers at the UC San Diego School of Medicine have launched a clinical trial to investigate the safety of neural stem cell transplantation in patients with chronic spinal cord injuries. This phase one clinical trial is recruiting eight patients for the 5-year study.

Joseph Ciacci, UC San Diego

“The goal of this study is to evaluate the safety of transplanting neural stem cells into the spine for what one day could be a treatment for spinal cord injuries,” said Joseph Ciacci, M.D., principal investigator and neurosurgeon at UC San Diego Health System. “The study’s immediate goal, however, is to determine whether injecting these neural stem cells into the spine of patients with spinal cord injury is safe.”

Related goals of the clinical trial include evaluating the stem cell graft’s survival and the effectiveness of immunosuppression drugs to prevent rejection. The researchers will also look for possible therapeutic benefits such as changes in motor and sensory function, bowel and bladder function, and pain levels.

Patients who are accepted for the study will have spinal cord injury to the T7-T12 level of the spine’s vertebrae and will have incurred their injury between one and two years ago.

All participants will receive the stem cell injection. The scientists will use a line of human stem cells approved by the U.S. FDA for human trials in patients with chronic traumatic spinal injuries. These cells were previously tested for safety in patients with amyotrophic lateral sclerosis (ALS).

Since stem cell transplantation for spinal cord injury is just beginning clinical tests, unforeseen risks, complications or unpredictable outcomes are possible. Careful clinical testing is essential to ensure that this type of therapy is developed responsibly with appropriate management of the risks that all medical therapies may present.

Pre-clinical studies of these cells by Ciacci and Martin Marsala, M.D., at the UC San Diego School of Medicine, showed that these grafted neural stem cells improved motor function in spinal cord injured rats with minimal side effects indicating that human clinical trials are now warranted.

This clinical trial at UC San Diego Health System is funded by Neuralstem Inc. and was launched and supported by the UC San Diego Sanford Stem Cell Clinical Center. The center was recently created to advance leading-edge stem cell medicine and science, protect and counsel patients, and accelerate innovative stem cell research into patient diagnostics and therapy.

To learn more about eligibility for this clinical trial, please call Amber Faulise at (858) 657-5175 or email her at rfaulise@ucsd.edu.

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How breast cancer usurps powers of mammary stem cells


Finding provides insight into how aggressive breast cancer might be treated.

Mammary cells found during pregnancy that express integrin beta3 (CD61) act as stem cells, capable of reconstituting a new mammary gland in mice. This property may be to blame for the more aggressive nature of beta3-expressing breast cancer cells. Shown is a section from a mammary “outgrowth” harvested at lactation and immuno-stained for the epithelial markers E-cadherin (brown) and alpha-SMA (red).

During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the UC San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer.

Writing in today’s (Aug. 11) issue of Developmental Cell, David A. Cheresh, Ph.D., Distinguished Professor of Pathology and vice chair for research and development, Jay Desgrosellier, Ph.D., assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy.

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated,” said Cheresh. “This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.”

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Grafted stem cells in rat spinal cord injuries show dramatic growth


Reprogrammed human neurons extend axons almost entire length of central nervous system.

mage depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.

Building upon previous research, scientists at the UC San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.

Writing in today’s (Aug. 7) early online edition of Neuron, lead scientist Paul Lu, Ph.D., of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses.

The iPSCs used were developed from a healthy 86-year-old human male.

“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, M.D., Ph.D., professor of neurosciences and director of the UC San Diego Center for Neural Repair.

For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.

While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.

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Single-cell analysis holds promise for stem cell, cancer research


UCSF researchers use microfluidic technology to probe human brain development.

Arnold Kriegstein, UC San Francisco

UC San Francisco researchers have identified cells’ unique features within the developing human brain, using the latest technologies for analyzing gene activity in individual cells, and have demonstrated that large-scale cell surveys can be done much more efficiently and cheaply than was previously thought possible.

“We have identified novel molecular features in diverse cell types using a new strategy of analyzing hundreds of cells individually,” said Arnold Kriegstein, M.D., Ph.D., director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. “We expect to use this approach to help us better understand how the complexity of the human cortex arises from cells that are spun off through cell division from stem cells in the germinal region of the brain.”

The research team used technology focused on a “microfluidic” device in which individual cells are captured and flow into nanoscale chambers, where they efficiently and accurately undergo the chemical reactions needed for DNA sequencing. The research showed that the number of reading steps needed to identify and spell out unique sequences and to successfully identify cell types is 100 times fewer than had previously been assumed. The technology, developed by Fluidigm Corp., can be used to individually process 96 cells simultaneously.

“The routine capture of single cells and accurate sampling of their molecular features now is possible,” said Alex Pollen, Ph.D., who along with fellow Kriegstein-lab postdoctoral fellow Tomasz Nowakowski, Ph.D., conducted the key experiments, in which they analyzed the activation of genes in 301 cells from across the developing human brain. Their results were published online August 3 in Nature Biotechnology.

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Stem cell agency awards two grants to UC researchers


Projects will address Limbal Stem Cell Deficiency and Huntington’s disease.

Two University of California researchers received bridge funding from the state’s stem cell agency totaling $1.2 million.

The California Institute for Regenerative Medicine’s governing board Thursday awarded UCLA researcher Sophie Deng almost $700,000 for work in developing a synthetic scaffold to be used in advancing knowledge of Limbal Stem Cell Deficiency, a blinding eye disorder, generally caused by damage to the cornea on the surface of the eye.

UC Irvine researcher Leslie Thompson was awarded more than $500,000 to conduct laboratory tests of a potential therapy for Huntington’s disease, a devastating and always fatal brain disorder. Currently there are no effective treatments for Huntington’s.

Deng and Thompson each had previously received funding from CIRM for their efforts.

In other stem cell news, a new stem cell discovery might one day lead to a more streamlined process for obtaining stem cells, which in turn could be used in the development of replacement tissue for failing body parts, according to UC San Francisco scientists who reported the findings in the current edition of Cell.

Embryonic stem cells can develop into a multitude of cells types. Researchers would like to understand how to channel that development into the specific types of mature cells that make up the organs and other structures of living organisms. One key seems to be long chains of sugars that dangle from proteins on surfaces of cells. Kamil Godula’s group at UC San Diego has created synthetic molecules that can stand in for the natural sugars, but can be more easily manipulated to direct the process, they report in the Journal of the American Chemical Society.

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New reprogramming method makes better stem cells


Findings provide insights into basic biology of stem cells.

Scanning electron micrograph of cultured human neuron from induced pluripotent stem cell. (Image courtesy of Mark Ellisman and Thomas Deerinck, UC San Diego)

A team of researchers from the UC San Diego School of Medicine, Oregon Health & Science University (OHSU), and Salk Institute for Biological Studies has shown for the first time that stem cells created using different methods produce differing cells. The findings, published in today’s (July 2) online issue of Nature, provide new insights into the basic biology of stem cells and could ultimately lead to improved stem cell therapies.

Capable of developing into any cell type, pluripotent stem cells offer great promise as the basis for emerging cell transplantation therapies that address a wide array of diseases and conditions, from diabetes and Alzheimer’s disease to cancer and spinal cord injuries. In theory, stem cells could be created and programmed to replace ailing or absent cells for every organ in the human body.

The gold standard is human embryonic stem cells (ES cells) cultured from discarded embryos generated by in vitro fertilization, but their use has long been limited by ethical and logistical considerations. Scientists have instead turned to two other methods to create stem cells: Somatic cell nuclear transfer (SCNT), in which genetic material from an adult cell is transferred into an empty egg cell, and induced pluripotent stem cells (iPS cells), in which adult cells are reverted back to a stem cell state by artificially turning on targeted genes.

Until now, no one had directly and closely compared the stem cells acquired using these two methods. The scientists found they produced measurably different results. “The nuclear transfer ES cells are much more similar to real ES cells than the iPS cells,” said co-senior author Louise Laurent, Ph.D., assistant professor in the Department of Reproductive Medicine at UC San Diego. “They are more completely reprogrammed and have fewer alterations in gene expression and DNA methylation levels that are attributable to the reprogramming process itself.”

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Heart muscle can regenerate itself in very limited amounts


UCLA researchers are first to directly measure division of cardiomyocytes.

Reza Ardehali, UCLA

Researchers from UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research are the first to directly measure the division of heart muscle cells, proving that while such division is very rare, it does occur.

The study, conducted by assistant professor of cardiology Dr. Reza Ardehali and colleagues, resolves a recent controversy over whether the heart muscle has the power to regenerate itself. The findings are also important for future research that could lead to the regeneration of heart tissue to repair damage caused by disease or heart attack.

The findings were published May 29 in Proceedings of the National Academy of Sciences.

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Link identified between stem cell regulation, development of lung cancer


UCLA findings could lead to new personalized treatments for lung cancer.

UCLA researchers led by Dr. Brigitte Gomperts have discovered the inner workings of the process thought to be the first stage in the development of lung cancer. Their study explains how factors that regulate the growth of adult stem cells that repair tissue in the lungs can lead to the formation of precancerous lesions.

Findings from the three-year study could eventually lead to new personalized treatments for lung cancer, which is responsible for an estimated 29 percent of U.S. cancer deaths, making it the deadliest form of the disease.

The study was published online today (June 19) in the journal Stem Cell. Gomperts, a member of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the UCLA Jonsson Comprehensive Cancer Center, collaborated with Manash Paul and Bharti Bisht, postdoctoral scholars and co-lead authors of the study.

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Stem cell therapy shows promise for MS in mouse model


Scientists at UC Irvine, Scripps Research Institute, University of Utah lead project.

Thomas Lane

Mice crippled by an autoimmune disease similar to multiple sclerosis regained the ability to walk and run after a team of researchers led by scientists at UC Irvine, the Scripps Research Institute and University of Utah implanted human stem cells into their injured spinal cords.

The mice started walking a couple of weeks after implantation, and they completely recovered over the next several months, according to the researchers.

Thomas Lane, an immunologist at the University of Utah who started the work when he was at UC Irvine, had never seen anything like it.

“We’ve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred,” said Lane, who had received a $4.8 million grant from the California Institute for Regenerative Medicine to support the work.

The mice’s dramatic recovery, which is reported online ahead of print by the journal Stem Cell Reports, could lead to new ways to treat multiple sclerosis in humans. “This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients,” said co-author Craig Walsh, a UC Irvine immunologist.

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$4M from Broad Foundation will support UCLA research


Two new gifts will benefit faculty in stem cell science and digestive diseases.

Two new gifts from The Eli and Edythe Broad Foundation to UCLA totaling $4 million will fund research in stem cell science and digestive diseases and support the recruitment of key faculty at two renowned research centers.

The gifts bring to $30 million The Broad Foundation’s total support of faculty recruitment and basic and translational research at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and at the Center for Inflammatory Bowel Diseases at UCLA’s Division of Digestive Diseases.

A $2 million gift to the Broad Stem Cell Research Center adds to The Broad Foundation’s original 2007 gift of $20 million, which has supported faculty and research and launched the Innovation Award program, which furthers cutting-edge research at the center by giving UCLA stem cell scientists “seed funding” for their research projects. The new gift will enable the continuation of the award program, which has yielded a 10-to-1 return on investment with grantees securing additional funding from other agencies, including the National Institutes of Health and more than $200 million in total grants from the California Institute for Regenerative Medicine, the state’s stem cell agency.

“The Broads’ generous support has been essential to the development of new therapies that are currently in, or very near, clinical trials for treating blindness, sickle cell disease and cancer,” said Dr. Owen Witte, director of the Broad Stem Cell Research Center. “The Broad Stem Cell Research Center’s work, supported by critical philanthropic and other resources, is quickly being translated from basic scientific discoveries into new cellular therapies that will change the practice of medicine and offer future treatment options for diseases thought to be incurable, such as muscular dystrophy, autism and AIDS.”

The $2 million gift to the Division of Digestive Diseases builds on nearly $6 million in previous commitments from The Broad Foundation since 2003.

The gifts have enabled the division to develop a comprehensive research and clinical enterprise focused on inflammatory bowel disease, one of only a few such centers in the world.  Earning a multifold return for The Broad Foundation’s initial investments, these grants have enabled investigators to secure $11 million in funding from pharmaceutical companies, the National Institutes of Health and nonprofit foundations.

In addition, The Broad Foundation’s Broad Medical Research Program has provided more than $600,000 in grants to UCLA researchers over the past decade for the study of inflammatory bowel disease.

The new gift will support the Center for Inflammatory Bowel Diseases and research led by Dr. Charalabos “Harry” Pothoulakis, the center’s director. Pothoulakis’ team conducts research aimed at identifying the molecular mechanisms involved in the development of this group of chronic debilitating diseases, for which there is no cure.

The researchers have led the way in revealing how neuropeptides and hormones contribute to inflammatory bowel diseases and the roles of obesity and fat tissue in their development. The team has created a unique human fat cell and fat tissue biobank, and its investigations hold great promise for the development of new drug treatments for Crohn’s disease and ulcerative colitis.

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Damage control: Recovering from radiation and chemotherapy


UC San Diego protein discovery could boost efficacy of bone marrow replacement treatments.

The continuous, necessary production of blood cells, including these red blood cells captured in a scanning micrograph by Thomas Deerinck, is the responsibility of hematopoietic stem cells found in bone marrow.

Researchers at the UC San Diego School of Medicine report that a protein called beta-catenin plays a critical, and previously unappreciated, role in promoting recovery of stricken hematopoietic stem cells after radiation exposure.

The findings, published in the May 1 issue of Genes and Development, provide a new understanding of how radiation impacts cellular and molecular processes, but perhaps more importantly, they suggest new possibilities for improving hematopoietic stem cell regeneration in the bone marrow following cancer radiation treatment.

Ionizing radiation exposure – accidental or deliberate – can be fatal due to widespread destruction of hematopoietic stem cells, the cells in the bone marrow that give rise to all blood cells. A number of cancer treatments involve irradiating malignancies, essentially destroying all exposed blood cells, followed by transplantation of replacement stem cells to rebuild blood stores. The effectiveness of these treatments depends upon how well the replacement hematopoietic stem cells do their job.

In their new paper, principal investigator Tannishtha Reya, Ph.D., professor in the department of pharmacology, and colleagues used mouse models to show that radiation exposure triggers activation of a fundamental cellular signaling pathway called Wnt in hematopoietic stem and progenitor cells.

“The Wnt pathway and its key mediator, beta catenin, are critical for embryonic development and establishment of the body plan,” said Reya. “In addition, the Wnt pathway is activated in stem cells from many tissues and is needed for their continued maintenance.”

The researchers found that mice deficient in beta-catenin lacked the ability to activate canonical Wnt signaling and suffered from impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. Specifically, mouse hematopoietic stem cells without beta-catenin could not suppress the production of oxidative stress molecules that damage cell structures. As a result, they could not recover effectively after radiation or chemotherapy.

“Our work shows that Wnt signaling is important in the mammalian hematopoietic system, and is critical for recovery from chemotherapy and radiation,” Reya said. “While these therapies can be life-saving, they take a heavy toll on the hematopoietic system from which the patient may not always recover.”

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