TAG: "Stem cells"

UC will lead effort to create library of brain cell activity


NIH program will advance fight against ALS, other neurodegenerative diseases.

Leslie Thompson, UC Irvine

UC Irvine will receive $8 million from the National Institutes of Health to establish one of six national centers dedicated to creating a database of human cellular responses that will accelerate efforts to develop new therapies for many diseases.

Leslie M. Thompson, UCI professor of psychiatry & human behavior and neurobiology & behavior, will partner with researchers from Cedars-Sinai Medical Center’s Regenerative Medicine Institute, the Gladstone Institute of Neurological Disease, UC San Francisco, Johns Hopkins University and the Massachusetts Institute of Technology.

They will study brain cell activity in motor neuron disorders including ALS and build a detailed archive of these disease “signatures” that identifies cell targets for new drug treatments. ALS, or amyotrophic lateral sclerosis, also called Lou Gehrig’s disease, attacks motor neurons, cells that control the muscles.

Overall, the NIH is awarding $64 million to six research groups to establish centers that support the Library of Integrated Network-Based Cellular Signatures program. The UC Irvine-based center will be called NeuroLINCS.

The goal of the LINCS program is to utilize the latest cutting-edge technology and scientific methods to catalog and analyze cellular function and molecular activity in response to perturbing agents – such as drugs and genetic factors – that have specific effects on cells. LINCS researchers will measure the cells’ tiniest molecular and biochemical responses and use computer analyses to uncover common patterns – called signatures. LINCS data will be freely available to any scientist.

“Human brain cells are far less understood than other cells in the body,” said Thompson, who’s affiliated with the Sue & Bill Gross Stem Cell Research Center and UCI MIND. “The collective expertise of NeuroLINCS investigators provides a unique opportunity to increase our knowledge of what makes brain cells unique and what happens during neurodegenerative diseases – with a strong focus toward effective treatments. We feel this will have broad application to a number of human brain diseases.”

She and her colleagues will study the effects, or signatures, of perturbing agents on induced pluripotent stem cell-derived neurons and glial cells from “unaffected” cells and those exhibiting the pathology of motor neuron diseases.

At UC Irvine, Thompson will work closely with the UCI Genomics High-Throughput Facility to explore gene expression patterns in these brain cells, which is expected to yield novel insights into pathways and gene networks that guide the development of cell signatures.

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Stem cell science takes bold step at UC San Diego


Three first-in-human clinical trials are underway.

A 26-year-old woman paralyzed after a motor vehicle accident a year ago has successfully undergone a first-in-human experimental procedure to test whether neural stem cells injected at the site of a spinal cord injury is safe and could be an effective treatment.

The procedure, conducted on Sept. 30 under the auspices of the Sanford Stem Cell Clinical Center at UC San Diego Health System and in collaboration with Neuralstem Inc., a Maryland-based biotechnology firm, is the first of four in the phase one clinical trial. Post safety testing, it’s hoped that the transplanted neural stem cells will develop into new neurons that bridge the gap created by the injury, replace severed or lost nerve connections and restore at least some motor and sensory function.

The patient, whose identity remains confidential for privacy reasons, has been discharged and is recovering without complication or adverse effects at home, said Joseph Ciacci, M.D., principal investigator and neurosurgeon at UC San Diego Health System.

The spinal cord injury trial is one of three recent groundbreaking stem cell efforts at UC San Diego, supported by the Sanford Stem Cell Clinical Center, to make the significant leap from laboratory to first-in-human clinical trials.

Last month, researchers at UC San Diego Moores Cancer Center and the Sanford Stem Cell Clinical Center launched a novel phase one trial to assess the safety of a monoclonal antibody treatment that targets cancer stem cells in patients with chronic lymphocytic leukemia, the most common form of blood cancer.

And later this month, the first patient is scheduled to receive an unprecedented stem cell-based therapy designed to treat type 1diabetes in another phase one clinical trial at UC San Diego.

“What we are seeing after years of work is the rubber hitting the road,” said Lawrence Goldstein, Ph.D., director of the UC San Diego Stem Cell program and Sanford Stem Cell Clinical Center at UC San Diego Health System. “These are three very ambitious and innovative trials. Each followed a different development path; each addresses a very different disease or condition. It speaks to the maturation of stem cell science that we’ve gotten to the point of testing these very real medical applications in people.”

To be sure, Goldstein said, the number of patients involved in these first trials is small. The initial focus is upon treatment with low doses to assess safety, but also with hope of patient benefit. As these trials progress – and additional trials are launched – Goldstein predicts greater numbers of patients will be enrolled at UC San Diego and the Sanford Stem Cell Clinical Center and elsewhere.

“Clinical trials are the safest way to pursue potential therapies. You want to prove that a new therapy will work for more than just a single, random patient.”

While stem cell-based trials are beginning to emerge around the country, Goldstein noted that San Diego continues to assert itself as a stem cell research hub and a leading force for translating basic discoveries into medical applications, now and in the future.

“These innovative trials are the result of some truly rare features you find at UC San Diego and in the region,” he said. “There is a unique sense of collaboration and communication here among scientists in academia, clinical medicine and the biotechnology industry. An enterprise like the Sanford Center can promote and accelerate the very complex processes of research, development and testing so that the right people make the right connections and the right ideas and trials get fast-tracked, but in a way that ensures fundamentally the safety of patients while striving for benefit.”

More about the three trials:

Neural stem cell transplants and spinal cord injuries
The Neuralstem phase one clinical trial, conducted over five years with four patients, is designed to assess the safety and efficacy of an approach that might, it is hoped, someday be a treatment for paralyzing spinal cord injuries.

In preclinical studies, Ciacci and Martin Marsala, M.D., a professor in the Department of Anesthesiology at UC San Diego School of Medicine and the Sanford Consortium for Regenerative Medicine, and colleagues grafted human neural stem cells into rats with spinal cord injuries. The introduced cells showed extensive growth and connected to remaining nerve cells near the injury site, resulting in significantly improved motor function with minimal side effects in animal models.

The goal now is to determine whether similar effects occur in human patients. The researchers will also test for possible therapeutic benefits, such as reduced paralysis and improvements in motor and sensory function, bowel and bladder function and pain levels.

VC-01 and Type 1 diabetes
In collaboration with ViaCyte Inc., a San Diego-based biotechnology firm specializing in regenerative medicine, UC San Diego researchers led by principal investigator Robert Henry, M.D., professor of medicine in the Division of Endocrinology and Metabolism at UC San Diego and chief of the Section of Endocrinology, Metabolism & Diabetes at the Veterans Affairs San Diego Healthcare System, have launched the first-ever phase one-two clinical trial of a stem cell-derived therapy for patients with Type 1 diabetes. The first procedure is planned for later this month, with a second tentatively scheduled in mid-November.

Type 1 diabetes mellitus is a life-threatening chronic condition in which the pancreas produces little or no insulin, a hormone needed to allow glucose to enter cells to produce energy. It is typically diagnosed during childhood or adolescence, but can also strike adults. Though far less common than Type 2 diabetes, which occurs when the body becomes resistant to insulin, Type 1 may affect up to 3 million Americans with emotionally and financially devastating consequences. Standard treatment involves daily injections of insulin and rigorous management of diet and lifestyle. Currently, there is no cure.

The two-year trial will involve approximately 40 study participants at four to six testing sites, with San Diego being first. The trial will assess the safety, tolerability and efficacy of varying doses of VC-01, which involves implanting specially encapsulated embryonic stem cell-derived cells under the skin of patients where it’s hoped they will safely mature into pancreatic beta and other cells able to produce a continuous supply of needed insulin and other substances.

Development and testing of VC-01 is funded, in part, by the California Institute for Regenerative Medicine (CIRM), Sanford Stem Cell Clinical Center and JDRF, formerly known as the Juvenile Diabetes Research Foundation. Clinical testing and coordination is provided by UC San Diego Clinical and Translational Research Institute.

Cirmtuzumab and leukemia
Researchers at UC San Diego Moores Cancer Center and the Sanford Stem Cell Clinical Center have launched a phase one human clinical trial to assess the safety and efficacy of a new monoclonal antibody for patients with chronic lymphocytic leukemia (CLL), the most common form of blood cancer in adults.

The drug, called cirmtuzumab, targets a molecule called ROR1 that normally is used only by embryonic cells during early development, but which is abnormally exploited by cancer cells to promote tumor growth and spread, otherwise known as metastasis. Metastasis is responsible for 90 percent of all cancer-related deaths.

Because ROR1 is not used by normal adult cells, scientists believe it is a unique marker of cancer cells in general and cancer stem cells in particular. ROR1 appears to drive tumor growth and disease spread and scientists think that presents an excellent novel target for anti-cancer therapy.

Cirmtuzumab was developed at Moores Cancer Center in the laboratory of Thomas Kipps, M.D., Ph.D., who led this effort as one of six projects initially funded through CIRM’s HALT leukemia grant to co-principal investigators Dennis Carson, M.D., and Catriona Jamieson, M.D., Ph.D.  The drug’s name acknowledges CIRM’s continued support in a “Disease Team III” award, which provides some of the resources needed for a clinical trial. The Leukemia and Lymphoma Society has also provided additional support.

The trial will involve patients with relapsed or refractory CLL receiving an intravenous infusion every 14 days at Moores Cancer Center, followed by regular monitoring and clinic visits to assess efficacy and identify and manage any adverse effects. Initial treatment is planned for two months.

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NCI grant awarded to study novel cancer treatment


UC Davis will study combining a novel type of immunotherapy with radiation, chemotherapy.

Robert Canter, UC Davis

A multidisciplinary team at UC Davis will embark on research to determine whether combining a novel type of immunotherapy with radiation and chemotherapy can make treatment for sarcoma, breast and pancreatic cancers more effective.

The work is funded with a $1.7 million, 5-year grant from the National Cancer Institute (NCI) and will involve the UC Davis Laboratory of Cancer Immunology in the Department of Dermatology, Division of Surgical Oncology, Department of Radiation Oncology, as well as the School of Veterinary Medicine.

“We think we have a novel and potentially high-impact treatment that can be developed fairly rapidly for clinical use,” said Robert Canter, associate professor of surgical oncology and a lead researcher on the project. The treatment would combine an immune therapy derived from natural killer cells with traditional drug and radiation therapy.

Sarcoma, breast and pancreas cancers were chosen for the study because they can be aggressive and difficult to treat, and they lend themselves to an approach in which tumor specimens can be examined before and after treatment to determine their efficacy, he said.

Impetus for the study comes from earlier research demonstrating the importance of natural killer cells, which develop in the bone marrow, in helping prevent relapse in patients who undergo stem cell transplants for treatment of leukemia and other diseases. Studies have shown that natural killer cells are important to the body’s natural defenses against virally-infected and malignant cells, and they help to regulate immune cell function.

“We know from studies in bone marrow transplantation that natural killer cells reject hematopoietic stem cells and prevent bone marrow engraftment, so we have hypothesized that natural killer cells can also target cancer stem cells, since there are similarities and shared properties between the hematopoietic stem cells and cancer stem cells,” Canter explained.

Because they are resistant to chemotherapy and radiation therapy, cancer stem cells can repopulate after treatment, causing relapses and cancer spread. The UC Davis researchers will use natural killer cells as a form of immune therapy to attack cancer stem cells.

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Seeing is believing


UC Santa Barbara’s Dennis Clegg is taking stem cell-based therapy for AMD to clinical trials.

Dennis Clegg, UC Santa Barbara

Age-related macular degeneration (AMD) is the leading cause of vision loss in the United States among people age 50 and older. It is estimated that 11 million people in the United States have some form of age-related macular degeneration, and the number is expected to double by 2050.

Pioneering research using stem cells to regenerate eye tissue conducted by UC Santa Barbara’s Dennis Clegg and co-workers may one day help people with AMD. As the first person to hold the newly endowed Wilcox Family Chair in BioMedicine, Clegg, a professor in UCSB’s Department of Molecular, Cellular and Developmental Biology, is poised to bring stem-cell-based therapy for AMD to phase one clinical trials.

Supported by a generous gift from UCSB alumni Sue and Gary Wilcox, the chair is designed to further pre-translational work on human biological systems that may lead to clinical studies.

“I am so grateful to Gary and Sue Wilcox for their generosity in creating the Wilcox Family Chair in BioMedicine,” said Clegg, who is also a co-founder of campus’s Center for Stem Cell Biology and Engineering. “It will help fund innovative, high-risk, high-gain research as well as provide seed money to support students and postdoctoral scholars.”

Clegg is also co-director of the California Project to Cure Blindness, a collaborative effort aimed at developing a stem-cell-based therapy for AMD. The project is funded by the California Institute for Regenerative Medicine (CIRM), the state’s stem cell agency. Partners in the project include the California Institute of Technology (Caltech), the University of Southern California (USC), the City of Hope and University College London.

AMD takes two forms: wet and dry. In the wet form, for which treatment is currently available, growth of abnormal blood vessels causes blood and fluid to leak into the retina, resulting in vision distortion, blind spots and, ultimately, loss of central vision.

The dry form of the disease, which has no treatment and is the focus of Clegg’s research, is caused by the presence of yellow deposits in the eye’s macula. As these deposits grow in size and increase in number, vision is dimmed and distorted. A concomitant thinning of the light-sensitive layer of cells in the macula eventually leads to the death of a cell type called retinal pigmented epithelium (RPE). These are the support cells for the rods and cones — the eyes’ photoreceptors, which allow light to be translated into recognizable images.

“It’s especially devastating because the visual defect occurs in the macula, which is the center of the retina,” Clegg explained. “That part is used for high acuity vision, so people with the disease end up with a big blank spot in the middle of their field of vision. Some reports estimate that more than 30 million people worldwide have this disease, so there is a real unmet medical need for a therapy.”

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Diabetes in a dish


With NIH grant, researchers hope to build bits of miniature pancreas.

Stem cells differentiating into pancreatic cells. Cells are made visible by blue dye. Transcription factors show in green and red.

Although type 1 diabetes can be controlled with insulin injections and lifestyle modifications, major advances in treating the disease have not been made in more than two decades and there remain fundamental gaps in what is understood about its causes and how to halt its progression.

With a 5-year, $4-million grant from the National Institutes of Health, researchers at the UC San Diego School of Medicine and bioengineers at UC San Diego Jacobs School of Engineering, with colleagues at UC Irvine and Washington University in St. Louis hope to change this.

The team’s goal is to bioengineer a miniature pancreas in a dish, not the whole pancreas but the organ’s irregularly shaped patches – called Islets of Langerhans – that regulate the body’s blood sugar levels.

“The bottleneck to new cures for type 1 diabetes is that we don’t have a way to study human beta cells outside of the human body,” said Maike Sander, M.D., professor in  the departments of pediatrics and cellular and molecular medicine and director of the Pediatric Diabetes Research Center at UC San Diego and Rady Children’s Hospital-San Diego. “If we are successful, we will for the first time be able to study the events that trigger beta cell destruction.”

Beta cells in islets secrete the hormone insulin. In patients with type 1 diabetes, the beta cells are destroyed and the body loses its ability to regulate blood sugar levels. Researchers, however, are unsure of the mechanism by which beta cells are lost. Some researchers believe that the disease may be triggered by beta cell apoptosis (self-destruction); others believe that the body’s immune system initiates attacks on these cells.

To actually bioengineer the pancreas’ endocrine system, researchers plan to induce human stem cells to develop into beta cells and alpha cells, as well as other cells in the islet that produce hormones important for controlling blood sugar levels. These cells will then be co-mingled with cells that make blood vessels and the cellular mass will be placed within a collagen matrix mimicking the pancreas. The matrix was developed by Karen Christman, Ph.D., associate professor of bioengineering at the Jacobs School of Engineering.

“Our previous work with heart disease has shown that organ-specific matrices help to create more mature heart cells in a dish,” Christman said. “I am really excited to apply the technology to diabetes research.”

If the pancreatic islets can be successfully bioengineered, researchers could conduct mechanistic studies of beta cell maturation, replication, reprogramming, failure and survival. They say new drug therapies could be tested in the 3-D culture. It also would be possible to compare beta cells from people with and without the disease to better understand the disease’s genetic component. Such work might eventually lead to treatments for protecting or replacing beta cells in patients.

The project is being funded through the National Institutes of Health Consortium on Human Islet Biomimetics.

Other grant co-recipients include Christopher Hughes, Ph.D., chair, Molecular Biology and Biochemistry School of Biological Sciences, UC Irvine; and Steven George, M.D., Ph.D., chair of the Department of Biomedical Engineering at Washington University in St. Louis.

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Drug targeting leukemia cells enters clinical trial


Antibody developed at UC San Diego.

Researchers at the UC San Diego School of Medicine have launched a phase one human clinical trial to assess the safety and efficacy of a new monoclonal antibody for patients with chronic lymphocytic leukemia (CLL), the most common form of blood cancer in adults.

The new antibody targets ROR1, a protein used by embryonic cells during early development and exploited by cancer cells to promote tumor growth and metastasis, the latter responsible for 90 percent of all cancer-related deaths.

Because ROR1 is not expressed by normal adult cells, scientists believe it is a biomarker of cancer cells in general and cancer stem cells in particular. Because it appears to drive tumor growth and disease spread, they believe it also presents an excellent target for anti-cancer therapy.

Developed at UC San Diego Moores Cancer Center by Thomas Kipps, M.D., Ph.D., who holds the Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues, the antibody is called cirmtuzumab (also known as UC-961). In previous animal studies, Kipps’ team reported that ROR1 is singularly expressed on CLL and also on a variety of different cancers, including cancers of the breast, pancreas, colon, lung and ovary. In mouse models of CLL, ROR1 acts as an accelerant when combined with another oncogene to produce a faster-growing, more aggressive cancer.

Cirmtuzumab was developed under the auspices of the California Institute for Regenerative Medicine’s HALT leukemia grant awarded to Dennis Carson, M.D., principal investigator, and Catriona Jamieson, M.D., Ph.D., co-principal investigator to develop six distinct therapies against cancer stem cells. Kipps led one of the six projects and generated antibodies against ROR1, leading to the cirmtuzumab trial in patients with CLL.

“The primary goal of this phase one clinical trial is to evaluate whether cirmtuzumab is a safe and well-tolerated cancer stem cell-targeted agent in patients with CLL,” said Jamieson, chief of the Division of Regenerative Medicine, associate professor of medicine, director of stem cell research at UC San Diego Moores Cancer Center, deputy director of the Sanford Stem Cell Clinical Center and a principal investigator of the cirmtuzumab clinical trial.

Michael Choi, M.D., assistant clinical professor of medicine and co-principal investigator of the clinical trial said, “The trial will involve patients with relapsed or refractory CLL, who will receive an intravenous infusion every 14 days at Moores, followed by regular monitoring and clinic visits to assess efficacy and identify and manage any adverse effects. Initial treatment is planned for two months.”

To learn more about eligibility for this clinical trial, call Reilly L. Kidwell at (858) 534-4801 or Samuel Zhang at (858) 534-8127.

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Neurochemical imbalance discovered in schizophrenia


Findings are an important step toward understanding chemical basis for schizophrenia.

Using human induced pluripotent stem cells (hiPSCs), researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego have discovered that neurons from patients with schizophrenia secrete higher amounts of three neurotransmitters broadly implicated in a range of psychiatric disorders.

The findings, reported online today (Sept. 11) in Stem Cell Reports, represent an important step toward understanding the chemical basis for schizophrenia, a chronic, severe and disabling brain disorder that affects an estimated one in 100 persons at some point in their lives. Currently, schizophrenia has no known definitive cause or cure and leaves no tell-tale physical marks in brain tissue.

“The study provides new insights into neurotransmitter mechanisms in schizophrenia that can lead to new drug targets and therapeutics,” said senior author Vivian Hook, Ph.D., a professor with Skaggs School of Pharmacy and UC San Diego School of Medicine.

In the study, UC San Diego researchers with colleagues at The Salk Institute for Biological Studies and the Icahn School of Medicine at Mount Sinai, N.Y., created functioning neurons derived from hiPSCs, themselves reprogrammed from skin cells of schizophrenia patients. The approach allowed scientists to observe and stimulate human neurons in ways impossible in animal models or human subjects.

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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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