TAG: "Stem cells"

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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Scientists develop method to define stages of stem cell programming


Research could have broad impact in improving disease modeling, devising new therapies.

By Peter Bracke, UCLA

Microscopic view of a colony of induced pluripotent stem cells obtained by reprogramming a specialized cell for two weeks. (Credit: UCLA Broad Stem Cell Research Center)

In a study that provides scientists with a critical new understanding of stem cell development and its role in disease, UCLA researchers led by Kathrin Plath, have established a first-of-its-kind methodology that defines the stages by which specialized cells are reprogrammed into stem cells resembling those found in embryos.

The study, conducted by researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, was published this month in the journal Cell.

Induced pluripotent stem cells, known as iPSCs, are cells that can be generated from adult cells and then, like embryonic stem cells, be directed to become any cell in the human body. Adult cells can also be reprogrammed in the lab to change from a specialized cell back to an iPSC (and thus becoming a cell similar to that of an embryonic stem cell).

Reprogramming takes one to two weeks and is a largely inefficient process, with typically less than one percent of the starting cells successfully becoming an iPSC. The exact stages a cell goes through during the reprogramming process are not well understood. This knowledge is important, as iPSCs hold great promise in the field of regenerative medicine, as they can reproduce indefinitely and provide a single source of patient-specific cells to replace those lost to injury or disease. They can also be used to create novel disease models from which new drugs and therapies can be developed.

Vincent Pasque and Jason Tchieu, postdoctoral fellows in Plath’s lab and co-first authors of the study, developed a roadmap of the reprogramming process using detailed time-course analyses. They induced the reprogramming of specialized cells (that could only make more of themselves, and not other cell types), then observed and analyzed on a daily basis or every other day the process of transformation at the single-cell level. The data was collected and recorded during a period of up to two weeks.

Plath’s team found that the changes that happen in cells during reprogramming occur in sequentially, and that importantly, the stages of the sequence were the same across the different reprogramming systems and different cell types analyzed.

“The exact stage of reprogramming of any cell can now be determined,” Pasque said. “This study signals a big change in thinking, because it provides simple and efficient tools for scientists to study stem cell creation in a stage-by-stage manner. Most studies to date ignore the stages of reprogramming, but we can now seek to better understand the entire process on both a macro and micro level.”

Plath’s team further discovered that the stages of reprogramming to iPSC are different from what was expected. They found that it is not simply the reversed sequence of stages of embryo development. Some steps are reversed in the expected order; others do not actually happen in the exact reverse order and resist a change until late during reprogramming to iPSCs.

“This reflects how cells do not like to change from one specialized cell type to another and resist a change in cell identity,” Pasque said. “Resistance to reprogramming also helps to explain why reprogramming takes place only in a very small proportion of the starting cells.”

With these findings, Plath’s lab plans future studies to actively isolate specific cell types during specific stages of reprogramming. They also hope the research will encourage further investigation into the characteristics of iPSC development.

“This research has broad impact, because by understanding cell reprogramming better we have the potential to improve disease modeling and the generation of better sources of patient-specific specialized cells suitable for replacement therapy,” said Plath, who is a professor of biological chemistry. “This can ultimately benefit patients with new and better treatments for a wide range of diseases.”

The research was supported by grants from the California Institute for Regenerative Medicine, the state’s stem cell agency. Additional funding was provided by the UCLA Broad Stem Cell Research Center through philanthropy and other sources.

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New stem cell technique shows promise in HIV resistance


UC Davis research paves way for human clinical trials using gene therapy.

Joseph Anderson, UC Davis

By Charles Casey, UC Davis

Using modified human stem cells, a team of UC Davis scientists has developed an improved gene therapy strategy that in animal models shows promise as a functional cure for the human immunodeficiency virus (HIV) that causes AIDS.  The achievement, which involves an improved technique to purify populations of HIV-resistant stem cells, opens the door for human clinical trials that were recently approved by the U.S. Food and Drug Administration.

“We have devised a gene therapy strategy to generate an HIV-resistant immune system in patients,” said Joseph Anderson, principal investigator of the study and assistant professor of internal medicine. “We are now poised to evaluate the effectiveness of this therapy in human clinical trials.”

Anderson and his colleagues modified human stem cells with genes that resist HIV infection and then transplanted a near-purified population of these cells into immunodeficient mice. The mice subsequently resisted HIV infection, maintaining signs of a healthy immune system.

The findings are now online in a paper titled “Safety and efficacy of a tCD25 pre-selective combination anti-HIV lentiviral vector in human hematopoietic stem and progenitor cells,” and will be published in the journal Stem Cells.

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A sense for biosensors


UC Irvine’s Weian Zhao has created a device that improves detection of bacterial, viral invaders in blood samples.

The Integrated Comprehensive Droplet Digital Detection system invented by Weian Zhao of UC Irvine converts blood samples directly into billions of very small droplets. (Photo by Steve Zylius, UC Irvine)

By Tom Vasich, UC Irvine

As a doctoral student at McMaster University in Hamilton, Ontario, Weian Zhao took part in a Canada-wide research effort to develop bioactive paper that would detect, capture and deactivate waterborne and airborne pathogens.

As part of this project, he helped invent gold nanoparticle-coated paper that could detect common pathogens, such as E. coli, but ultimately, the product didn’t meet his exacting standards of diagnostic speed and sensitivity. With a freshly minted Ph.D. in chemistry, Zhao moved on to a joint postdoctoral fellowship at both the Massachusetts Institute of Technology and Harvard, where he dove into stem cell research, his biosensor work seemingly left north of the border.

But the challenge of creating a technology that could rapidly and selectively identify bacterial and viral invaders in blood samples nagged at the young scientist, even as he joined UC Irvine in 2011 as an assistant professor of pharmaceutical sciences with state-of-the-art lab space in the Sue & Bill Gross Stem Cell Research Center.

And then he met Enrico Gratton. In his Laboratory for Fluorescence Dynamics, the UCI biomedical engineer and colleagues have been developing imaging tools for biomedical applications. Among them is a three-dimensional particle counter that tags low-concentration fluorescent particles in large volumes of solution within several minutes, which drew Zhao’s attention. He knew he was back in the biosensor game.

Employing this particle counter, Zhao created a bloodstream infection test that speeds up diagnosis times with unprecedented accuracy – allowing physicians to treat patients with potentially deadly ailments more promptly and effectively.

Zhao says that the Integrated Comprehensive Droplet Digital Detection system can, in as little as 90 minutes, detect bacteria in milliliters of blood with single-cell sensitivity; no cell culture is needed. He published his latest results in the November issue of Nature Communications.

“We are extremely excited about this technology because it addresses a long-standing unmet medical need in the field,” says Zhao, who also holds a faculty appointment in biomedical engineering. “As a platform technology, it may have many applications in detecting extremely low-abundance biomarkers in other areas, such as cancers, HIV and, most notably, Ebola.”

Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages.

Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with incipient blood infections.

The Integrated Comprehensive Droplet Digital Detection technology differs from other diagnostic techniques in that it converts blood samples directly into billions of very small droplets. Fluorescent DNA sensor solution infused into the droplets detects those with bacterial markers, lighting them up with an intense fluorescent signal. Zhao says that separating the samples into so many small drops minimizes the interference of other components in blood, making it possible to directly identify target bacteria without the purification typically required in conventional assays.

“The IC 3D instrument is designed to read a large volume in each measurement, to speed up diagnosis,” Gratton says. “Importantly, using this technique, we can detect a positive hit from hundreds of millions of measurement samples with very high confidence.”

But invention was only the first step. Zhao wants to commercialize IC 3D. At UCI, faculty researchers with an entrepreneurial bent can work with the Institute for Innovation, an interdisciplinary and campuswide center focused on integrating research, entrepreneurship and technology to create real-world applications that benefit the public and drive the economy. The Office of Technology Alliances, part of the institute, helped Zhao patent-protect the IC 3D technology and establish a spin-off company, Velox Biosystems, to test and manufacture a commercial IC 3D device.

Currently, Zhao is focusing on applying IC 3D to cancer treatments – an extension of the research he’s been advancing since joining UCI.

Zhao has been developing stem cell messengers that selectively migrate to cancer sites to deliver tumor-fighting drugs or probes for contrast-enhanced medical imaging. This could, potentially, enable the identification of cancer micro-metastases at their early stages and increase the effectiveness of chemotherapeutic treatments for metastatic cancer while mitigating the symptoms associated with systemic chemotherapy.

For this work, Zhao was included in the MIT Technology Review’s 2012 list of the world’s top innovators under the age of 35, and this year he earned a prestigious National Institutes of Health Director’s New Innovator Award to further his efforts to create stem cell-based detection methods and treatments for cancer.

He’s also collaborating with Dr. Jason Zell, an assistant professor of medicine and co-leader of the Colon Cancer Disease-Oriented Team at UCI’s Chao Family Comprehensive Cancer Center, to use IC 3D to identify biomarkers in colon cancers. This could enable oncologists to gauge the effectiveness of treatment during the cancer’s early stages more accurately than with current methods, which Zell says are not reliable.

Zhao is now seeking business partners to accelerate Velox Biosystems’ growth and hopes to conduct clinical studies of IC 3D’s utility in patient diagnosis and treatment.

“That’s what’s so important about this project,” he says. “We’ve created a multi-platform tool that has the potential to work with a variety of infections and diseases. I’m very excited about its future.”

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Researchers ID protein key to harnessing regenerative power of blood stem cells


Discovery could lead to development of more effective therapies for blood diseases, cancers.

By Peter Bracke, UCLA

UCLA scientists have for the first time identified a protein that plays a key role in regulating how blood stem cells replicate in humans.

This discovery lays the groundwork for a better understanding of how this protein controls blood stem cell growth and regeneration, and could lead to the development of more effective therapies for a wide range of blood diseases and cancers.

The study, which was led by Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member Dr. John Chute, was published online last month ahead of print in the Journal of Clinical Investigation.

Hematopoietic stem cells (HSCs) are the blood-forming cells that have the remarkable capacity to both self-renew and give rise to all of the differentiated cells (fully developed cells) of the blood system. HSC transplantation provides curative therapy for thousands of patients annually. However, little is known about the process through which transplanted HSCs replicate following their arrival in human bone marrow. In this study, the authors showed that a cell surface protein called protein tyrosine phosphatase-sigma (PTP-sigma) regulates the critical process called engraftment, which is how HSCs start to grow and make healthy blood cells after transplantation.

Mamle Quarmyne, a graduate student Chute’s lab and first author of the study, demonstrated that PTP-sigma is produced (expressed) on a high percentage of mouse and human HSCs. She showed further that genetic deletion of PTP-sigma in mice markedly increased the ability of HSCs to engraft in transplanted mice.

In a complementary study, Quarmyne demonstrated that selection of human blood HSCs which did not express PTP-sigma led to a 15-fold increase in HSC engraftment in transplanted immune-deficient mice. Taken together, these studies showed that PTP-sigma suppresses normal HSC engraftment capacity and targeted blocking of PTP-sigma can substantially improve mouse and human HSC engraftment after transplantation.

Chute and colleagues showed further that PTP-sigma regulates HSC function by suppressing a protein, RAC1, which is known to promote HSC engraftment after transplantation.

“These findings have tremendous therapeutic potential since we have identified a new receptor on HSCs, PTP-sigma, which can be specifically targeted as a means to potently increase the engraftment of transplanted HSCs in patients,” said Chute, senior author of the study and professor of hematology/oncology and radiation oncology at UCLA. “This approach can also potentially accelerate hematologic recovery in cancer patients receiving chemotherapy and/or radiation, which also suppress the blood and immune systems.”

Chute’s team is now working with fellow UCLA researchers to test small molecules for their ability to specifically inhibit PTP-sigma on blood stem cells. If these studies are successful, they aim to translate these findings into clinical trials in the near future.

This research was supported by funding from the National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute. Additional funding was provided by the UCLA Broad Stem Cell Research Center through philanthropy and other sources.

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Novel mechanism of RNA regulation in embryonic stem cells discovered


UCLA research suggests new strategy to control cellular identity and fate.

Yi Xing, UCLA

By Stuart Wolpert, UCLA

A team of scientists that included researchers from UCLA has discovered a novel mechanism of RNA regulation in embryonic stem cells. The findings are strong evidence that a specific chemical modification, or “tag,” on RNA plays a key role in determining the ability of embryonic stem cells to adopt different cellular identities.

The team also included scientists from Harvard Medical School, Massachusetts General Hospital and Stanford University.

Published in the journal Cell Stem Cell, the research reveals that depleting or knocking out a key component of the machinery that places this chemical tag — known both as m6A and N6-methyladenosine — on RNA significantly blocks embryonic stem cells from differentiating into more specialized types of cells.

A key property of embryonic stem cells is their ability to differentiate into many specialized types of cells. However, instead of marching toward a specific fate when prompted by signals to differentiate, embryonic stem cells that have reduced ability to place m6A become stuck in a sort of suspended animation, even though they appear healthy.

Yi Xing, a UCLA associate professor of microbiology, immunology and molecular genetics, led the informatics analyses and was a co-corresponding author of the paper. Other corresponding authors were Dr. Cosmas Giallourakis, an assistant professor of medicine at Harvard Medical School and Massachusetts General Hospital, and Dr. Howard Chang, a professor of Stanford University’s School of Medicine and a Howard Hughes Medical Institute investigator.

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How stem cells can be activated to help immune system fight infection


UCLA scientists show crucial role of genes Scalloped and Yorkie.

UCLA researchers have discovered that the Scalloped (above) and Yorkie genes play a key role in how progenitor stem cells are activated to fight infection. (Image by Dr. Julian Martinez-Agosto Lab, UCLA)

By Peter Bracke, UCLA

In a study led by Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member Dr. Julian Martinez-Agosto, UCLA scientists have shown that two genes not previously known to be involved with the immune system play a crucial role in how progenitor stem cells are activated to fight infection.

This discovery lays the groundwork for a better understanding of the role progenitor cells can play in immune system response and could lead to the development of more effective therapies for a wide range of diseases.

The two-year study was published in the current issue of the journal Current Biology.

Progenitor cells are the link between stem cells and fully differentiated cells of the blood system, tissues and organs. This maturation process, known as differentiation, is determined in part by the original environment that the progenitor cell came from, called the niche. Many of these progenitors are maintained in a quiescent state or “standby mode” and are ready to differentiate in response to immune challenges such as stress, infection or disease.

Dr. Gabriel Ferguson, a postdoctoral fellow in Martinez-Agosto’s lab and first author of the study, built upon the lab’s previous research that utilized the blood system of the fruit fly species Drosophila to show that a specific set of signals must be received by progenitor cells to activate their differentiation into cells that can work to fight infection after injury. Ferguson focused on two genes previously identified in stem cells but not in the blood system, named Yorkie and Scalloped, and discovered that they are required in a newly characterized cell type called a lineage specifying cell. These cells then essentially work as a switch, sending the required signal to progenitor cells.

The researchers further discovered that when the progenitor cells did not receive the required signal, the fly would not make the mature cells required to fight infection. This indicates that the ability of the blood system to fight outside infection and other pathogens is directly related to the signals sent by this new cell type.

“The beauty of this study is that we now have a system in which we can investigate how a signaling cell uses these two genes, Yorkie and Scalloped, which have never before been shown in blood, to direct specific cells to be made,” said Martinez-Agosto, associate professor of human genetics. “It can help us to eventually answer the question of how our body knows how to make specific cell types that can fight infection.”

The researchers said that they hope future studies will examine these genes beyond Drosophila and extend to mammalian models, and that the system will be used by the research community to study the role of the genes Yorkie and Scalloped in different niche environments.

“At a biochemical level, there is a lot of commonality between the molecular machinery in Drosophila and that in mice and humans,” Ferguson said. “This study can further our shared understanding of how the microenvironment can regulate the differentiation and fate of a progenitor or stem cell.”

Martinez-Agosto noted, “Looking at the functionality of these genes and their effect on the immune response has great potential for accelerating the development of new targeted therapies.”

Ferguson’s research on this project was supported by a Cellular and Molecular Biology National Institutes of Health predoctoral training grant. Additional funding was provided by the David Geffen School of Medicine at UCLA.

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Researchers ID protein key to development of blood stem cells


Critical step in improving stem cell therapies for blood-related diseases and cancers.

By Peter Bracke, UCLA

Led by Dr. Hanna Mikkola, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA scientists have discovered a protein that is integral to the self-replication of hematopoietic stem cells during human development.

The discovery lays the groundwork for researchers to generate hematopoietic stem cells in the lab that better mirror those that develop in their natural environment. This could in turn lead to improved therapies for blood-related diseases and cancers by enabling the creation of patient-specific blood stem cells for transplantation.

The findings are reported online ahead of print in the journal Cell Stem Cell.

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