TAG: "Stem cells"

UC researchers awarded stem cell grants


Funding to develop treatments for Huntington’s, spina bifida, chronic diabetic wounds.

Roslyn Rivkah Isseroff, UC Davis

University of California researchers from two campuses received three grants totaling more than $12 million in funding from the state’s stem cell agency to develop stem cell treatments for Huntington’s disease, spina bifida and chronic diabetic wounds.

The funding was part of $25.2 million in Preclinical Development Awards targeting seven deadly or disabling disorders – what the California Institute for Regenerative Medicine considers “the most promising” research leading up to human clinical trials using stem cells to treat disease and injury.

UC Davis researchers were awarded a pair of grants totaling more than $7 million to develop stem cell therapies for spina bifida ($2.2 million) and chronic diabetic wounds ($5 million).

Diana Farmer, professor and chair of surgery at UC Davis Medical Center, is developing a placental stem cell therapy for spina bifida, the common and devastating birth defect that causes lifelong paralysis as well as bladder and bowel incontinence. She and her team are working on a unique treatment that can be applied in utero – before a baby is born — in order to reverse spinal cord damage.

Diana Farmer, UC Davis

Roslyn Rivkah Isseroff, a UC Davis professor of dermatology, and Jan Nolta, professor of internal medicine and director of the university’s Stem Cell Program, are developing a wound dressing containing stem cells that could be applied to chronic wounds and be a catalyst for rapid healing. This is Isseroff’s second CIRM grant, and it will help move her research closer to having a product approved by the U.S. Food and Drug Administration that specifically targets diabetic foot ulcers, a condition affecting more than 6 million people in the country.

Also, Leslie Thompson of the Sue & Bill Gross Stem Cell Research Center at UC Irvine has been awarded $5 million to continue her CIRM-funded effort to develop stem cell treatments for Huntington’s disease. The grant supports her next step: identifying and testing stem cell-based treatments for HD, an inherited, incurable and fatal neurodegenerative disorder. In this project, Thompson and her colleagues will create an HD therapy employing human embryonic stem cells that can be evaluated in clinical trials.

Leslie Thompson, UC Irvine

CIRM’s governing board also approved an application for the Tools and Technology Award that had been deferred from the January meeting. UCLA’s Carla Koehler will now get $1.3 million for research on a small molecule tool for reducing the malignant potential in reprogramming human induced pluripotent stem cells and embryonic stem cells.

Overall, CIRM’s governing board has awarded nearly $1.9 billion in stem cell grants, with half of the total going to the University of California or UC-affiliated institutions.

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‘Open’ stem cell chromosomes reveal new possibilities for diabetes


UC San Diego researchers map chromosomal changes over time.

Pancreatic cells derived from embryonic stem cells.

By Heather Buschman, UC San Diego

Stem cells hold great promise for treating a number of diseases, in part because they have the unique ability to differentiate, specializing into any one of the hundreds of cell types that comprise the human body. Harnessing this potential, though, is difficult. In some cases, it takes up to seven carefully orchestrated steps of adding certain growth factors at specific times to coax stem cells into the desired cell type. Even then, cells of the intestine, liver and pancreas are notoriously difficult to produce from stem cells. Writing in Cell Stem Cell today (April 2), researchers at the UC San Diego School of Medicine have discovered why.

It turns out that the chromosomes in laboratory stem cells open slowly over time, in the same sequence that occurs during embryonic development. It isn’t until certain chromosomal regions have acquired the “open” state that they are able to respond to added growth factors and become liver or pancreatic cells. This new understanding, say researchers, will help spur advancements in stem cell research and the development of new cell therapies for diseases of the liver and pancreas, such as type 1 diabetes.

“Our ability to generate liver and pancreatic cells from stem cells has fallen behind the advances we’ve made for other cell types,” said Maike Sander, M.D., professor of pediatrics and cellular and molecular medicine and director of the Pediatric Diabetes Research Center at UC San Diego. “So we haven’t yet been able to do things like test new drugs on stem cell-derived liver and pancreatic cells. What we have learned is that if we want to make specific cells from stem cells, we need ways to predict how those cells and their chromosomes will respond to the growth factors.”

Sander led the study, together with co-senior author Bing Ren, Ph.D., professor of cellular and molecular medicine at UC San Diego and Ludwig Cancer Research member.

Chromosomes are the structures formed by tightly wound and packed DNA. Humans have 46 chromosomes – 23 inherited from each parent. Sander, Ren and their teams first made maps of chromosomal modifications over time, as embryonic stem cells differentiated through several different developmental intermediates on their way to becoming pancreatic and liver cells. Then, in analyzing these maps, they discovered links between the accessibility (openness) of certain regions of the chromosome and what they call developmental competence – the ability of the cell to respond to triggers like added growth factors.

“We’re also finding that these chromosomal regions that need to open before a stem cell can fully differentiate are linked to regions where there are variations in certain disease states,” Sander says.

In other words, if a person were to inherit a genetic variation in one of these chromosomal regions and his or her chromosome didn’t open up at exactly the right time, he or she could hypothetically be more susceptible to a disease affecting that cell type. Sander’s team is now working to further investigate what role, if any, these chromosomal regions and their variations play in diabetes.

Co-authors of this study also include Allen Wang, Ruiyu Xie, Thomas Harper, Nisha A. Patel, Kayla Muth, Jeffrey Palmer, Jinzhao Wang, and Dieter K. Lam, UC San Diego; Feng Yue, The Pennsylvania State University; Yan Li, Yunjiang Qiu, Ludwig Cancer Research; and Jeffrey C. Raum, Doris A. Stoffers, University of Pennsylvania.

This research was funded, in part, by the National Institutes of Health (grants U01-DK089567, U01-DK072473, U01-ES017166, U01-DK089540 and T32-DK7494-27), California Institute for Regenerative Medicine (grants RB5-07236 and TG2-01154, Bridges to Stem Cells Program), Helmsley Charitable Trust and JDRF.

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UCSF team finds key to making neurors from stem cells


Pnky, noncoding RNA found in brain stem cells, may have range of clinical applications.

In this cluster of neurons, the greens cells have been infected with a virus to reduce levels of the RNA molecule called Pnky, resulting in increased production of neurons. Someday this finding could be important for regenerative medicine and cancer treatment.

By Steve Tokar

A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.

The research, led by neurosurgeon Daniel A. Lim, M.D., Ph.D., and published today (March 19) in Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer’s disease, Parkinson’s disease and traumatic brain injury, and in cancer treatment.

Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.

The name, pronounced “Pinky,” was inspired by the popular American cartoon series Pinky and the Brain. “Pnky is encoded near a gene called ‘Brain,’ so it sort of suggested itself to the students in my laboratory,” said Lim. Pnky also appears only to be found in the brain, he noted.

Co-first authors Alex Ramos, Ph.D., and Rebecca Andersen, who are students in Lim’s laboratory, first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.

“It is remarkable that when you take Pnky away, the stem cells produce many more neurons,” said Lim, an assistant professor of neurological surgery and director of restorative surgery at UCSF. “These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment.”

Lim observed that Pnky has an intriguing possible connection with brain tumors.

Using an analytical technique called mass spectrometry, Ramos found that Pnky binds the protein PTBP1, which is also found in brain tumors and is known to be a driver of brain tumor growth. In neural stem cells, Pnky and PTBP1 appear to function together to suppress the production of neurons. “Take away one or the other and the stem cells differentiate, making more neurons,” said Lim. “It is also possible that Pnky can regulate brain tumor growth, which means we may have identified a target for the treatment of brain tumors.”

Lim said that the larger significance of the research is that it adds to a growing store of knowledge about lncRNAs, previously unknown sections of the genome that some biologists have referred to as the “dark matter” of the human genome.

“Recently, over 50,000 human lncRNAs have been discovered. Thus, there may be more human lncRNAs than there are genes that code for proteins,” said Lim. “It is possible that not all lncRNAs have important biological functions, but we are making a start toward learning which ones do, and if so, how they function. It’s a new world of experimental biology, and the students in my lab are right there on the frontier.”

Lim had particular praise for Ramos, an M.D.-Ph.D. student in the UCSF Medical Scientist Training Program, and Andersen, who has a fellowship from the prestigious National Science Foundation (NSF) Graduate Research Fellowship Program. “They have been a great collaborative team and an inspiration to others in my lab,” said Lim. “I think they represent the pioneering, investigative spirit of the UCSF student body.”

Co-authors of the study are Siyuan John Liu, Tomasz Jan Nowakowski, Sung Jun Hong, Caitlin Gertz, Ryan D. Salinas, Hosniya Zarabi and Arnold Kriegstein, M.D., Ph.D., all of UCSF.

The study was supported by funds from the National Institutes of Health, U.S. Department of Veterans Affairs, NSF, UCSF, San Francisco State University and the Howard Hughes Medical Institute.

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Even at molecular level, taking it slow helps us cope with stress


UC Berkeley scientists ID new molecular pathway critical to aging.

Illustration of a mitochondrion, a cell’s energy station. Within mitochondria are a multitude of proteins, which must be folded properly to function. UC Berkeley research has linked stress from mitochondrial misfolded proteins to blood stem cell aging, and they found a way to help the cells cope with the damage.

By Sarah Yang, UC Berkeley

UC Berkeley scientists have identified a new molecular pathway critical to aging, and confirmed that the process can be manipulated to help make old blood like new again.

The researchers found that blood stem cells’ ability to repair damage caused by inappropriate protein folding in the mitochondria, a cell’s energy station, is critical to their survival and regenerative capacity.

The discovery, to be published in the March 20 issue of the journal Science, has implications for research on reversing the signs of aging, a process thought to be caused by increased cellular stress and damage.

“Ultimately, a cell dies when it can’t deal well with stress,” said study senior author Danica Chen, an assistant professor in the Department of Nutritional Sciences and Toxicology. “We found that by slowing down the activity of mitochondria in the blood stem cells of mice, we were able to enhance their capacity to handle stress and rejuvenate old blood. This confirms the significance of this pathway in the aging process.”

Mitochondria host a multitude of proteins that need to be folded properly to function correctly. When the folding goes awry, the mitochondrial unfolded-protein response, or UPRmt, kicks in to boost the production of specific proteins to fix or remove the misfolded protein.

Chen’s lab stumbled upon the importance of UPRmt in blood stem cell aging while studying a class of proteins known as sirtuins, which are increasingly recognized as stress-resistance regulators.

The researchers noticed that levels of one particular sirtuin, SIRT7, increase as a way to help cells cope with stress from misfolded proteins in the mitochondria. Notably, SIRT7 levels decline with age.

There has been little research on the UPRmt pathway, but studies in roundworms suggest that its activity increases when there is a burst of mitochondrial growth.

Chen noted that adult stem cells are normally in a quiescent, standby mode with little mitochondrial activity. They are activated only when needed to replenish tissue, at which time mitochondrial activity increases and stem cells proliferate and differentiate. When protein-folding problems occur, however, this fast growth could lead to more harm.

“We isolated blood stem cells from aged mice and found that when we increased the levels of SIRT7, we were able to reduce mitochondrial protein-folding stress,” said Chen. “We then transplanted the blood stem cells back into mice, and SIRT7 improved the blood stem cells’ regenerative capacity.”

The new study found that blood stem cells deficient in SIRT7 proliferate more. This faster growth is due to increased protein production and increased activity of the mitochondria, and slowing things down appears to be a critical step in giving cells time to recover from stress, the researchers found. Chen likened this to an auto accident or stalled car jamming traffic on a freeway.

“You can deal with this congestion by removing all the cars that are blocked, but you can also stop more cars from getting onto the freeway,” she said. “When there’s a mitochondrial protein-folding problem, there is a traffic jam in the mitochondria. If you prevent more proteins from being created and added to the mitochondria, you are helping to reduce the jam.”

Until this study, it was unclear which stress signals regulate the transition of stem cells to and from the quiescent mode, and how that related to tissue regeneration during aging.

“Identifying the role of this mitochondrial pathway in blood stem cells gives us a new target for controlling the aging process,” said Chen.

UC Berkeley co-lead authors of the study are postdoctoral researcher Mary Mohrin and graduate students Jiyung Shin, Yufei Liu and Katharine Brown.

The National Institutes of Health, Ellison Medical Foundation, Glenn Foundation, National Science Foundation and Siebel Stem Cell Institute helped support this research.

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Boosting a natural protection against Alzheimer’s


Combining investigational therapy with gene variant may reduce dangers from brain plaques.

By Christina Johnson and Scott LaFee, UC San Diego

Researchers at the UC San Diego School of Medicine have identified a gene variant that may be used to predict people most likely to respond to an investigational therapy under development for Alzheimer’s disease (AD). The study, published today (March 12) in Cell Stem Cell, is based on experiments with cultured neurons derived from adult stem cells.

“Our results suggest that certain gene variants allow us to reduce the amount of beta amyloid produced by neurons,” said senior author Lawrence Goldstein, Ph.D., director of UC San Diego Sanford Stem Cell Clinical Center and UC San Diego Stem Cell Program. “This is potentially significant for slowing the progression of Alzheimer’s disease.” AD is the most common cause of dementia in the United States, afflicting one in nine people age 65 and older.

The genetic risk factor investigated are variants of the SORL1 gene. The gene codes for a protein that affects the processing and subsequent accumulation of beta amyloid peptides, small bits of sticky protein that build up in the spaces between neurons. These plaques are linked to neuronal death and related dementia.

Previous studies have shown that certain variants of the SORL1 gene confer some protection from AD, while other variants are associated with about a 30 percent higher likelihood of developing the disease. Approximately one-third of the U.S. adult population is believed to carry the non-protective gene variants.

The study’s primary finding is that variants in the SORL1 gene may also be associated with how neurons respond to a natural compound in the brain that normally acts to protect nerve cell health. The protective compound, called BDNF, short for brain-derived neurotrophic factor, is currently being investigated as a potential therapy for a number of neurological diseases, including AD, because of its role in promoting neuronal survival.

For the study, UC San Diego researchers took skin cells from 13 people, seven of whom had AD and six of whom were healthy control subjects, and reprogrammed the skin cells into stem cells. These stem cells were coaxed to differentiate into neurons, and the neurons were cultured and then treated with BDNF.

The experiments revealed that neurons that carried disease-protective SORL1 variants responded to the therapy by reducing their baseline rate of beta amyloid peptide production by, on average, 20 percent. In contrast, the neurons carrying the risk variants of the gene, showed no change in baseline beta amyloid production.

“BDNF is found in everyone’s brain,” said first author Jessica Young, Ph.D., a postdoctoral fellow in the Goldstein laboratory. “What we found is that if you add more BDNF to neurons that carry a genetic risk factor for the disease, the neurons don’t respond. Those with the protective genetic profile do.”

“The value of this kind of stem cell study is that it lets us probe the uniquely human aspects of disease and identify how a person’s DNA might determine their drug response, in this case to a potential treatment for Alzheimer’s,” Young said. “Future clinical trials on BDNF should consider stratifying patients based on their SORL1 risk factor and likelihood of benefiting from the therapy.”

Co-authors include Jonathan Boulanger-Weill, Daniel A. Williams, Grace Woodruff, Floyd Buen, Arra C. Revilla, Cheryl Herrera, Mason A. Israel, Shauna H. Yuan, and Steven D. Edland, all at UC San Diego.

Funding for the study was provided, in part, by the California Institute of Regenerative Medicine, A.P. Gianinni Foundation for Medical Research, BrightFocus Foundation and the National Institutes of Health (grant 2P50AG005131-31).

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Bioengineers put human hearts on chip to aid drug screening


Chips ultimately could replace use of animals to screen drugs for safety, efficacy.

By Sarah Yang, UC Berkeley

When UC Berkeley bioengineers say they are holding their hearts in the palms of their hands, they are not talking about emotional vulnerability.

Instead, the research team led by bioengineering professor Kevin Healy is presenting a network of pulsating cardiac muscle cells housed in an inch-long silicone device that effectively models human heart tissue, and they have demonstrated the viability of this system as a drug-screening tool by testing it with cardiovascular medications.

This organ-on-a-chip, reported in a study published today (March 9) in the journal Scientific Reports, represents a major step forward in the development of accurate, faster methods of testing for drug toxicity. The project is funded through the Tissue Chip for Drug Screening Initiative, an interagency collaboration launched by the National Institutes of Health to develop 3-D human tissue chips that model the structure and function of human organs.

“Ultimately, these chips could replace the use of animals to screen drugs for safety and efficacy,” said Healy.

The study authors noted a high failure rate associated with the use of nonhuman animal models to predict human reactions to new drugs. Much of this is due to fundamental differences in biology between species, the researchers explained. For instance, the ion channels through which heart cells conduct electrical currents can vary in both number and type between humans and other animals.

“Many cardiovascular drugs target those channels, so these differences often result in inefficient and costly experiments that do not provide accurate answers about the toxicity of a drug in humans,” said Healy. “It takes about $5 billion on average to develop a drug, and 60 percent of that figure comes from upfront costs in the research and development phase. Using a well-designed model of a human organ could significantly cut the cost and time of bringing a new drug to market.”

The heart cells were derived from human-induced pluripotent stem cells, the adult stem cells that can be coaxed to become many different types of tissue.

The researchers designed their cardiac microphysiological system, or heart-on-a-chip, so that its 3-D structure would be comparable to the geometry and spacing of connective tissue fiber in a human heart. They added the differentiated human heart cells into the loading area, a process that Healy likened to passengers boarding a subway train at rush hour. The system’s confined geometry helps align the cells in multiple layers and in a single direction.

Microfluidic channels on either side of the cell area serve as models for blood vessels, mimicking the exchange by diffusion of nutrients and drugs with human tissue. In the future, this setup also could allow researchers to monitor the removal of metabolic waste products from the cells.

“This system is not a simple cell culture where tissue is being bathed in a static bath of liquid,” said study lead author Anurag Mathur, a postdoctoral scholar in Healy’s lab and a California Institute for Regenerative Medicine fellow. “We designed this system so that it is dynamic; it replicates how tissue in our bodies actually gets exposed to nutrients and drugs.”

Within 24 hours after the heart cells were loaded into the chamber, they began beating on their own at a normal physiological rate of 55 to 80 beats per minute.

The researchers put the system to the test by monitoring the reaction of the heart cells to four well-known cardiovascular drugs: isoproterenol, E-4031, verapamil and metoprolol. They used changes in the heart tissue’s beat rate to gauge the response to the compounds.

The baseline beat rate for the heart tissue consistently fell within 55 to 80 beats per minute, a range considered normal for adult humans. They found that the responses after exposure to the drugs were predictable. For example, after half an hour of exposure to isoproterenol, a drug used to treat bradycardia (slow heart rate), the beat rate of the heart tissue increased from 55 to 124 beats per minute.

The researchers noted that their heart-on-a-chip could be adapted to model human genetic diseases or to screen for an individual’s reaction to drugs. They also are studying whether the system could be used to model multi-organ interactions. A standard tissue culture plate could potentially feature hundreds of microphysiological cell culture systems.

“Linking heart and liver tissue would allow us to determine whether a drug that initially works fine in the heart might later be metabolized by the liver in a way that would be toxic,” said Healy.

The engineered heart tissue remained viable and functional over multiple weeks. Given that time, it could be used to test various drugs, Healy said.

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Stem cell researchers develop promising method to treat sickle cell disease


Stem cell gene therapy technique leads to production of healthy blood cells.

By Mirabai Vogt-James, UCLA

UCLA stem cell researchers have shown that a novel stem cell gene therapy method could lead to a one-time, lasting treatment for sickle cell disease — the nation’s most common inherited blood disorder.

Published March 2 in the journal Blood, the study led by Dr. Donald Kohn of the UCLA Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research outlines a method that corrects the mutated gene that causes sickle cell disease and shows, for the first time, that the gene correction method leads to the production of normal red blood cells.

People with sickle cell disease are born with a mutation in their beta-globin gene that causes blood stem cells — which are made in the bone marrow — to produce rigid red blood cells that resemble a crescent or ‘sickle’ shape. These abnormally shaped red blood cells do not move smoothly through blood vessels, resulting in insufficient oxygen to vital organs.

The stem cell gene therapy method described in the study seeks to correct the mutation in the beta-globin gene so bone marrow stem cells produce normal, circular-shaped blood cells. The technique used specially engineered enzymes, called zinc-finger nucleases, to eliminate the mutated genetic code and replace it with a corrected version that repairs the beta-globin mutation.

The research showed that the method holds the potential to permanently treat the disease if a higher level of correction is achieved.

“This is a very exciting result,” said Dr. Kohn, professor of pediatrics and microbiology, immunology and molecular genetics. “It suggests the future direction for treating genetic diseases will be by correcting the specific mutation in a patient’s genetic code. Since sickle cell disease was the first human genetic disease where we understood the fundamental gene defect, and since everyone with sickle cell has the exact same mutation in the beta-globin gene, it is a great target for this gene correction method.”

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How stem cells are grown affects their genetic stability


Methods to multiply pluripotent cells for potential therapies raise worries about cancer.

By Scott LaFee, UC San Diego

The therapeutic promise of human stem cells is indisputably huge, but the process of translating their potential into effective, real-world treatments involves deciphering and resolving a host of daunting complexities.

Writing in today’s (Feb. 25) online issue of the journal PLOS ONE, researchers at the UC San Diego School of Medicine, with collaborators from The Scripps Research Institute (TSRI), have definitively shown for the first time that the culture conditions in which stem cells are grown and mass-produced can affect their genetic stability.

“Since genetic and epigenetic instability are associated with cancers, we worry that similar alterations in stem cells may affect their safety in therapeutic transplants. Certain mutations might make transplanted stem cells more likely to form tumors, introducing the risk of cancer where it didn’t exist before,” said co-corresponding author Louise Laurent, M.D., Ph.D., assistant professor and director of perinatal research in the Department of Reproductive Medicine at UC San Diego School of Medicine.

“This study shows the importance of quality control,” added Jeanne F. Loring, Ph.D., professor and director of the Center for Regenerative Medicine at TSRI, and adjunct professor in the UC San Diego Department of Reproductive Medicine and the study’s other co-corresponding author. “It’s almost certain these cells are safe, but we want to make sure they are free from any abnormalities.”

To exploit the transformative powers of human pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, requires producing them in large numbers for transplantation into patients.

“During this culturing process, mutations can occur, and mutations that increase cell survival or proliferation may be favored, such that the cells carrying such mutations could take over the culture,” said Laurent.

Human pluripotent stem cells are cultured in several different ways. Key variables are the surfaces upon which the cells are cultured, called the substrate, and the methods used to transfer cells from one culture dish into another as they grow, called the passage method.

Originally, scientists determined that stem cells grew best when cultured atop of a “feeder” layer that included other types of cells, such as irradiated mouse embryonic fibroblasts. For reasons not fully understood, these cells provide stem cells with factors that support their growth. However, concerns about the feeder cells also introducing undesirable materials into stem cells has prompted development of feeder-free cultures.

Moving cells from one culture dish to another has traditionally been done manually, with technicians physically separating the cultured cells into small clumps with an instrument. “It’s very labor-intensive,” said Laurent, “so new methods that use enzymes to separate individual cells were created.”

In the PLOS ONE paper, Laurent and colleagues compared stem cells grown on two substrates (with and without feeder cells) and passaged using manual and enzymatic methods. They report that the use of enzymes to passage the stem cells was strongly associated with increased genetic instability. Some of the mutations observed in the stem cells were previously known, but Laurent said others were seen for the first time, including deletion of a region of the genome that includes the gene P53, which is frequently deleted in cancer cells.

“I think these results call into question the use of enzymatic passaging, at least with enzymes that separate the cultures into single cells, for clinical use. However, we don’t want to imply that any culture method is absolutely ‘safe.’ Any new culture method should be evaluated for its impact on genetic stability, and every batch of cells destined for the clinic should be tested using sensitive high-resolution methods for detecting genetic alterations.

“The processes used to maintain and expand stem cell cultures for cell replacement therapies need to be improved, and the resulting cells must be carefully tested before use.”

Co-authors include Ibon Gariaonandia, Gerald K. Wambua, Heather L Schultheisz, Shannon Waltz, Yu-Chieh Wang, Ha Tran, Kristopher Nazor, Ileana Slavin, Candace Lynch and Ron Coleman, TSRI; Karen Sabatini, Francesca S. Boscolo, Trevor R. Leonardo and Gulsah Altun, TSRI and UCSD; Irene Gallego Romero, University of Chicago; David Reynolds and Steve Dalton, University of Georgia, Athens; and Hadar Amir, Robert Morey, Mana Parast and Yingchun Li, UCSD.

Funding for this research came, in part, from the California Institute for Regenerative Medicine (grants CL1-00502, RT1-01108, TR1-01250, RM1-01717, TB1-01193, TG2-01165), the National Institutes of Health (grants R33MH087925, P01GM085354, P01HL089471), the UC San Diego Department of Reproductive Medicine, the Hartwell Foundation, the Millipore Foundation, the Esther O’Keefe Foundation, the Marie Mayer Foundation, Autism Speaks, the Pew Charitable Trust and the Wellcome Trust.

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Human neural stem cells restore cognitive functions impaired by chemotherapy


UC Irvine study reveals how they alleviate ‘chemobrain’ after cancer treatments.

Charles Limoli, UC Irvine

By Tom Vasich, UC Irvine

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to UC Irvine researchers.

In preclinical studies using rodents, they found that stem cells transplanted one week after the completion of a series of chemotherapy sessions restored a range of cognitive functions, as measured one month later using a comprehensive platform of behavioral testing. In contrast, rats not treated with stem cells showed significant learning and memory impairment.

The frequent use of chemotherapy to combat multiple cancers can produce severe cognitive dysfunction, often referred to as “chemobrain,” which can persist and manifest in many ways long after the end of treatments in as many as 75 percent of survivors – a problem of particular concern with pediatric patients.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said Charles Limoli, a UCI professor of radiation oncology.

Study results appear in the Feb. 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

Many chemotherapeutic agents used to treat disparate cancer types trigger inflammation in the hippocampus, a cerebral region responsible for many cognitive abilities, such as learning and memory. This inflammation can destroy neurons and other cell types in the brain.

Additionally, these toxic compounds damage the connective structure of neurons, called dendrites and axons, and alter the integrity of synapses – the vital links that permit neurons to pass electrical and chemical signals throughout the brain. Limoli compares the process to a tree being pruned of its branches and leaves.

Consequently, the affected neurons are less able to transmit important neural messages that underpin learning and memory.

“In many instances, people experience severe cognitive impairment that’s progressive and debilitating,” Limoli said. “For pediatric cancer patients, the results can be particularly devastating, leading to reduced IQ, asocial behavior and diminished quality of life.”

For the UCI study, adult neural stem cells were transplanted into the brains of rats after chemotherapy. They migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

Importantly, Limoli and his colleagues found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Munjal Acharya, Lori-Ann Christie, Vahan Martirosian, Nicole N. Chmielewski, Nevine Hanna, Katherine Tran, Alicia Liao and Vipan Parihar of UCI contributed to the study, which was funded by the National Institutes of Health (grant R01 NS074388581) and supported by UCI’s Institute for Clinical & Translational Science.

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Building mini-brains to study disorders caused by HIV, meth use


UC San Diego scientist wins $2.5M award to create stem cell-derived models.

By Scott LaFee, UC San Diego

A UC San Diego School of Medicine project involving the creation of miniature models of the human brain – developed with stem cells – to study neurological disorders caused by HIV and methamphetamine use has been named one of five recipients of the 2015 Avant-Garde Award for HIV/AIDS Research from the National Institute on Drug Abuse (NIDA).

The project, headed by Tariq M. Rana, Ph.D., professor of pediatrics, will receive $500,000 per year for five years.

“The human cerebral cortex has evolved strikingly compared to those of other species, and no animal model accurately captures human-specific brain functions,” said Rana. “The creation of mini-brains, or organoids, will permit, for the first time, study of the toxic effects of addiction and HIV on the human brain in a dish. This offers us the exciting opportunity to design patient-specific model systems, which could potentially revolutionize drug discovery and precision medicine for central nervous system disorders.”

The Avant-Garde Awards are granted to scientists who propose high-impact research that could open new avenues for prevention and treatment of HIV/AIDS among drug abusers. The term “avant-garde” is used to describe highly innovative approaches that have the potential to be transformative.

“Despite the success of combined antiretroviral therapies, HIV remains a chronic disease with a host of debilitating side effects that are exacerbated in those suffering from substance use disorders,” said NIDA Director Nora D. Volkow, M.D.  “These scientists have proposed creative approaches that could transform the way we think about HIV/AIDS research, and could lead to the development of exciting new tools and strategies to prevent infections and improve the lives of substance abusers infected with HIV.”

The other 2015 recipients are:

  • Don C. Des Jarlais, Ph.D., Mount Sinai Beth Israel
  • Eli Gilboa, Ph.D., University of Miami School of Medicine
  • Nichole Klatt, Ph.D., University of Washington, Seattle
  • Alan D. Levine, Ph.D., Case Western Reserve University

For more information about the Avant-Garde Award Program and 2015 recipients, visit drugabuse.gov/about-nida.

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UC awarded $15M in stem cell grants


10 recipients from six campuses for Tools and Technologies Awards.

Laura Marcu, UC Davis

University of California researchers from six campuses received 10 grants totaling nearly $15 million in the latest round of funding from the state’s stem cell agency.

The funding was part of almost $30 million in new Tools and Technologies Awards for 20 projects announced at the California Institute for Regenerative Medicine’s monthly meeting. The Tools and Technologies Awards are intended to create and test novel tools and technologies, to improve existing ones, and to help resolve problems that are holding back the field.

Overall, CIRM’s governing board has awarded more than $1.8 billion in stem cell grants, with half of the total going to the University of California or UC-affiliated institutions.

Tools and Technologies Awards:

  • UC Berkeley: $1.4 million: David Schaffer
  • UC Davis: $3.7 million: Kent Leach, Laura Marcu
  • UC Irvine: $2.5 million: Mathew Blurton-Jones, Leif Havton
  • UCLA: $3.2 million: James Dunn, Hanna Mikkola
  • UC San Diego: $2.8 million: Shaochen Chen, Shyni Varghese
  • UC San Francisco: $1.4 million: Andrew Leavitt

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Treating non-healing bone fractures with stem cells


UC Davis tests device that offers a new approach to obtaining stem cells during surgery.

Mark Lee, UC Davis

By Charles Casey, UC Davis

UC Davis surgeons have launched a “proof-of-concept” clinical trial to test the safety and efficacy of a device that can rapidly concentrate and extract young cells from the irrigation fluid used during orthopaedic surgery. The new approach holds promise for improving the delivery of stem cell therapies in cases of non-healing fractures.

“People come to me after suffering for six months or more with a non-healing bone fracture, often after multiple surgeries, infections and hospitalizations,” said Mark Lee, associate professor of orthopaedic surgery, who is principal investigator on the clinical trial. “Stem cell therapy for these patients can be miraculous, and it is exciting to explore an important new way to improve on its delivery.”

About 6 million people suffer fractures each year in North America, according to the American Academy of Orthopaedic Surgeons. Five to 10 percent of those cases involve patients who either have delayed healing or fractures that do not heal. The problem is especially troubling for the elderly because a non-healing fracture significantly reduces a person’s function, mobility and quality of life.

Stem cells – early cells that can differentiate into a variety of cell types – have been used for several years to successfully treat bone fractures that otherwise have proven resistant to healing. Applied directly to a wound site, stem cells help with new bone growth, filling gaps and allowing healing and restoration of function. However, obtaining stem cells ready to be delivered to a patient can be problematic. The cells ideally come from a patient’s own bone marrow, eliminating the need to use embryonic stem cells or find a matched donor.

But the traditional way of obtaining these autologous stem cells – that is, stem cells from the same person who will receive them – requires retrieving the cells from a patient’s bone marrow, a painful surgical procedure involving general anesthesia, a large needle into the hip and about a week of recovery.

In addition, the cells destined to become healing blood vessels must be specially isolated from the bone marrow before they are ready to be transplanted back into the patient, a process that takes so long it requires a second surgery.

The device Lee and his UC Davis colleagues are now testing processes the “wastewater” fluid obtained during an orthopaedic procedure, which makes use of a reamer-irrigator-aspirator (RIA) system to enlarge a patient’s femur or tibia by high-speed drilling, while continuously cooling the area with water. In the process, bone marrow cells and tiny bone fragments are aspirated and collected in a filter to transplant back into the patient. Normally, the wastewater is discarded.

Although the RIA system filter captures the patient’s own bone and bone marrow for use in a bone graft or fusion, researchers found that the discarded effluent contained abundant mesenchymal stem cells as well as hematopoietic and endothelial progenitor cells, which have the potential to make new blood vessels, and potent growth factors important for signaling cells for wound healing and regeneration. The problem, however, was that the RIA system wastewater was too diluted to be useful.

Now, working with a device developed by SynGen Inc., a Sacramento-based biotech company specializing in regenerative medicine applications, the UC Davis orthopaedic team can take the wastewater and spin it down to isolate the valuable stem cell components. About the size of a household coffee maker, the device will be used in the operating room to rapidly produce a concentration of stem cells that can be delivered to a patient’s non-union fracture during a single surgery.

“The device’s small size and rapid capabilities allow autologous stem cell transplantation to take place during a single operation in the operating room rather than requiring two procedures separated over a period of weeks,” said Lee. “This is a dramatic difference that promises to make a real impact on wound healing and patient recovery.”

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