TAG: "Stem cells"

UC Grad Slam winners make research accessible one pitch at a time

Graduate students captivate audience by keeping it simple.

UC Irvine's Ashley Fong delivers the top-prize-winning presentation at the UC Grad Slam on using stem cells to mend damaged hearts. (Photos by Robert Durell)

By Nicole Freeling

>>Watch UC Grad Slam and individual students’ presentations

It took UC Irvine graduate student Ashley Fong years to make significant advances in her research using stem cells to repair damaged heart muscle, but just minutes — three to be exact — to wow a panel of judges with a succinct explanation of her work and capture the championship at the first UC-wide Grad Slam tournament.

Graduate students are rarely rewarded for being brief or simple, but those were the exact requirements to win Monday, as 10 UC scientists and scholars competed to deliver the most illuminating three-minute explanation of their work.

An elated Fong took home $6,000 in prize money and the glory of out-talking her peers — all of whom had won similar contests at their home campuses and provided some tough competition.

Coming in second and third place were Daniel Hieber of UC Santa Barbara and Alex Phan of UC San Diego, with talks on efforts to save a language from extinction and a device to help glaucoma patients.

“I have experience speaking at conferences,” Fong said. “But those are long talks, with dozens of slides, to a roomful of experts.”

She participated in Grad Slam, she said, to learn to communicate her work and why it matters to people outside the field. That skill is a growing necessity for researchers everywhere, as public funding for research and higher education grows ever more competitive. In such a climate, academics who can articulate the value of their research have an important edge. Grad Slam was aimed at giving master’s and Ph.D. students important career-building skills, while offering the public a window into the breadth of work being done across UC campuses.

Contestants spent weeks preparing, taking workshops and working one-on-one with coaches to hone their ideas, craft the structure of their talk and present extremely complex ideas in a way that would be relatable to a general audience.

By the time they took to the stage Monday, the students had honed their presentations to a fine point. Most were also well-versed in speaking in front of an audience, having competed in several qualifying rounds before taking the top prize on each of their campuses.

Public speaking did not come naturally at first, said Phan, a graduate student in mechanical and aerospace engineering. “But once you take this on, it stops being quite so uncomfortable. You begin to build up your confidence.”

The effort paid off: Phan won third place for his talk Fight for Sight, about an implantable pressure sensor that provides continuous monitoring for glaucoma patients. Phan ultimately hopes to patent the technology and bring it to market. When the award was announced, Phan’s parents, who had traveled from Los Angeles to watch the competition, leapt from their seats. “We are so proud of him,” said his mother.

UC Grad Slam winners Alex Phan, left, third place; Ashley Fong, first place; and Daniel Hieber, second place.

Learning to demystify their research

“Making the mysteries of basic research more understandable and accessible to the public is one of my priorities, and part of our responsibility as the nation’s premier public research university,” said UC President Janet Napolitano, who served as the event emcee. “Grad Slam plays a key role in highlighting the broad, societal significance of research at UC.”

Non-academics, including NBC Bay Area News anchor Jessica Aguirre, Silicon Valley venture capitalist Josh Green and Oakland Mayor Libby Schaaf, joined UC Regent Eddie Island and UC Provost Aimée Dorr as the contest judges. They evaluated contestants based on their ability to clearly and concisely explain their research and its impact.

The judges had a difficult task in determining the winner from a field of students, all of whom came across as polished, engaging and passionate about their pursuits.

“It’s been so great to be able to explain my research to people in my church, to my friends,” said UCLA master’s student Jean Paul Santos, who told the audience about a small, more powerful antennae he is engineering to help NASA scientists communicate directly with the Mars rover. “I had to figure out, how can I share the novelties of my research without going overboard or over your head?”

UC Riverside plant pathologist Jeannette Rapicavoli, who is a first-generation college student, said the experience had helped her better explain her research to her family. “It was like: ‘So this is why you want to be in college for nine years. We can understand it now.’”

Students described new insights into how species behave, how to help crops withstand drought, and how food waste can be harnessed as a source of fuel.

Reviving a dead language

Daniel Hieber, a linguistics Ph.D. student and the lone competitor not in a science, technology or engineering field, took second place for his talk about how he has helped to revive a language in the Louisiana bayou whose last native speakers died in the 1930s. From wax audio recordings of their voices, along with written archives, Hieber has reconstructed the Chitimacha language, even creating a Rosetta Stone audio tape, which tribal members now listen to in their cars.

“For the first time in 70 years, you can hear Chitimacha being spoken again in the schools and communities of the bayou,” Hieber said.

Following each of the presentations, Napolitano bantered with researchers, asking them about how they got interested in their line of research. “The work you’re doing represents years of serious research. But there’s no reason we can’t have a little fun,” she said.

UC Davis food scientist Ryan Dowdy described how as a boy, he would mix together water, oil and food coloring as a kid and sell it on the street, instead of the usual lemonade.

“I charged 50 cents. I made a killing.”

Dowdy and his peers represent an emerging breed of researchers, who are breaking down the stereotype of the elite intellectual, said National Public Radio contributor Sandra Tsing Loh, who teaches a science communications class at UC Irvine and had come to cheer contestants on. The public is hungry, Lo said, for scholars and scientists who can unleash the excitement of their discoveries.

Far from fitting the image of the aloof scientist, Grad Slam contestants described their passion pursuing advances that directly touch the lives of Californians and people elsewhere.

Fong described the mantra she uses when the rigors and frustrations of research overwhelm her. It was the same one she used at Grad Slam to get herself primed for the competition. “When I need to ground myself, I just remember, I want to save lives. That’s the reason I got into research.”

Related links:

CATEGORY: SpotlightComments Off

Cells that become sperm or eggs are vulnerable during pregnancy

UCLA research delivers new data for stem cell scientists to more accurately study infertility.

Male prenatal germline cells stained in green. (Image by UCLA Broad Stem Cell Research Center)

By Mirabai Vogt-James, UCLA

UCLA scientists examining causes of human infertility have found that the cells that create eggs or sperm during the prenatal stage of development are vulnerable to damage, according to new research published today (May 21).

The study by Amander Clark, of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, was published in the journal Cell. Clark said that the findings advance the understanding of human germ cells, which are responsible for carrying parents’ genes to a child. Abnormalities in the germ cells can cause infertility as well as diseases such as germ cell tumors in young boys and primary ovarian insufficiency in young girls.

“My overall research goal is to understand the causes of human infertility, so taking a close look at how germ cells develop in the embryo is crucial,” said Clark, associate professor and vice chair of molecular, cell and developmental biology in the life sciences at UCLA. “We know very little about how prenatal germline cells are made in the body. I am working to understand what they are sensitive to during development and what is protecting them from external environmental factors that could cause them to not work properly.”

The genetic information in all healthy cells is protected by a process called methylation, which acts as a coat on the genome that safeguards cells from mutations. Methylation removal happens infrequently in the human body, but one such time is during the prenatal stage of pregnancy. Clark’s study recorded the amount, duration and location of demethylation in prenatal germ cells from 53 to 137 days of development. The study, which was supported by grants from the National Institutes of Health and the California Institute for Regenerative Medicine, as well as the UCLA Broad Stem Cell Research Center, found that the human germline erases almost all evidence of genome methylation by 113 days of prenatal development.

View UCLA release

CATEGORY: NewsComments (0)

Stem cell model reveals cues critical to neurovascular unit formation

Real-time tracking of cellular behavior during human development provides new insights.

Autonomic neurons (green) co-patterning with blood vessels (red).

By Heather Buschman, UC San Diego

Crucial bodily functions we depend on but don’t consciously think about — things like heart rate, blood flow, breathing and digestion — are regulated by the neurovascular unit.

The neurovascular unit is made up of blood vessels and smooth muscles under the control of autonomic neurons. Yet how the nervous and vascular systems come together during development to coordinate these functions is not well understood.

Using human embryonic stem cells, researchers at the UC San Diego School of Medicine and Moores Cancer Center and Sanford-Burnham Medical Research Institute created a model that allows them to track cellular behavior during the earliest stages of human development in real-time. The model reveals, for the first time, how autonomic neurons and blood vessels come together to form the neurovascular unit.

The study is published today (May 21) by Stem Cell Reports.

“This new model allows us to follow the fate of distinct cell types during development, as they work cooperatively, in a way that we can’t in intact embryos, individual cell lines or mouse models,” said co-senior author of the study David Cheresh, Ph.D., Distinguished Professor of Pathology, vice-chair for research and development and associate director for translational research at UC San Diego. “And if we’re ever going to use stem cells to develop new organ systems, we need to know how different cell types come together to form complex and functional structures such as the neurovascular unit.”

The neurovascular unit comprises three cells types: endothelial cells, which form the blood vessel (vascular) tube; smooth muscle cells, which cover the endothelial tube and control vascular tone; and autonomic neurons, which influence the smooth muscle’s ability to contract and maintain vascular tone.

The study revealed that separate signals produced by endothelial cells and smooth muscle cells are required for embryonic cells to differentiate into autonomic neurons. The researchers discovered that endothelial cells secrete nitric oxide, while smooth muscle cells use the protein T-cadherin to interact with the neural crest, specialized embryonic cells that give rise to portions of the nervous system and other organs. The combination of endothelial cell nitric oxide and the T-cadherin interaction is sufficient to coax neural crest cells into becoming autonomic neurons, where they can then co-align with developing blood vessels.

In addition to answering long-standing questions about human development and improving the odds that scientists will one day be able to generate artificial organs from stem cells, this new insight on the autonomic nervous system also has implications for rare inherited conditions such as neurofibromatosis, tuberous sclerosis and Hirschsprung’s disease.

“These observations may help to explain certain human disease syndromes in which abnormalities of the nervous system appear to be associated, for previously unclear reasons, with vascular abnormalities,” said co-senior author Evan Snyder, M.D., Ph.D., professor and director of the Center for Stem Cells and Regenerative Medicine at Sanford-Burnham. “Furthermore, we demonstrate here that modeling human development and disease in the lab must take into account multiple cell types in order to reflect the actual human condition. We can no longer rely on merely examining pure populations of one cell type or another.”

Co-authors include Lisette M. Acevedo, Jeffrey N. Lindquist, UC San Diego and Sanford-Burnham; Breda M. Walsh, Peik Sia, UC San Diego; Flavio Cimadamore, Connie Chen, Martin Denzel, Cameron D. Pernia, Barbara Ranscht, and Alexey Terskikh, Sanford-Burnham.

This research was funded, in part, by the National Institutes of Health (grants K01CA148897 and P20GM075059) and California Institute for Regenerative Medicine (grants CIRM-CL1-00511-1 and CIRM-RB3-02098).

View UC San Diego article

CATEGORY: NewsComments (0)

Drug perks up old muscles, aging brains

UC Berkeley finding could lead to drug interventions for humans.

A small-molecule drug may hold the key to fitter muscle and brain as we age. (Credit: iStock)

By Robert Sanders, UC Berkeley

Whether you’re brainy, brawny or both, you may someday benefit from a drug found to rejuvenate aging brain and muscle tissue.

Researchers at the University of California, Berkeley, have discovered that a small-molecule drug simultaneously perks up old stem cells in the brains and muscles of mice, a finding that could lead to drug interventions for humans that would make aging tissues throughout the body act young again.

“We established that you can use a single small molecule to rescue essential function in not only aged brain tissue but aged muscle,” said co-author David Schaffer, director of the Berkeley Stem Cell Center and a professor of chemical and biomolecular engineering. “That is good news, because if every tissue had a different molecular mechanism for aging, we wouldn’t be able to have a single intervention that rescues the function of multiple tissues.”

The drug interferes with the activity of a growth factor, transforming growth factor beta 1 (TGF-beta1), that Schaffer’s UC Berkeley colleague Irina Conboy showed over the past 10 years depresses the ability of various types of stem cells to renew tissue.

“Based on our earlier papers, the TGF-beta1 pathway seemed to be one of the main culprits in multi-tissue aging,” said Conboy, an associate professor of bioengineering. “That one protein, when upregulated, ages multiple stem cells in distinct organs, such as the brain, pancreas, heart and muscle. This is really the first demonstration that we can find a drug that makes the key TGF-beta1 pathway, which is elevated by aging, behave younger, thereby rejuvenating multiple organ systems.”

The UC Berkeley team reported its results in the current issue of the journal Oncotarget. Conboy and Schaffer are members of a consortium of faculty who study aging within the California Institute for Quantitative Biosciences (QB3).

Depressed stem cells lead to aging

Aging is ascribed, in part, to the failure of adult stem cells to generate replacements for damaged cells and thus repair the body’s tissues. Researchers have shown that this decreased stem cell activity is largely a result of inhibitory chemicals in the environment around the stem cell, some of them dumped there by the immune system as a result of chronic, low-level inflammation that is also a hallmark of aging.

In 2005, Conboy and her colleagues infused old mice with blood from young mice – a process called parabiosis – reinvigorating stem cells in the muscle, liver and brain/hippocampus and showing that the chemicals in young blood can actually rejuvenate the chemical environment of aging stem cells. Last year, doctors began a small trial to determine whether blood plasma from young people can help reverse brain damage in elderly Alzheimer’s patients.

Such therapies are impractical if not dangerous, however, so Conboy, Schaffer and others are trying to track down the specific chemicals that can be used safely and sustainably for maintaining the youthful environment for stem cells in many organs. One key chemical target for the multi-tissue rejuvenation is TGF-beta1, which tends to increase with age in all tissues of the body and which Conboy showed depresses stem cell activity when present at high levels.

Five years ago, Schaffer, who studies neural stem cells in the brain, teamed up with Conboy to look at TGF-beta1 activity in the hippocampus, an area of the brain important in memory and learning. Among the hallmarks of aging are a decline in learning, cognition and memory. In the new study, they showed that in old mice, the hippocampus has increased levels of TGF-beta1 similar to the levels in the bloodstream and other old tissue.

Using a viral vector that Schaffer developed for gene therapy, the team inserted genetic blockers into the brains of old mice to knock down TGF-beta1 activity, and found that hippocampal stem cells began to act more youthful, generating new nerve cells.

Drug makes old tissue cleverer

The team then injected into the blood a chemical known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta1. This small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent, successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever, Conboy said.

“The key TGF-beta1 regulatory pathway became reset to its young signaling levels, which also reduced tissue inflammation, hence promoting a more favorable environment for stem cell signaling,” she said. “You can simultaneously improve tissue repair and maintenance repair in completely different organs, muscle and brain.”

The researchers noted that this is only a first step toward a therapy, since other biochemical cues also regulate adult stem cell activity. Schaffer and Conboy’s research groups are now collaborating on a multi-pronged approach in which modulation of two key biochemical regulators might lead to safe restoration of stem cell responses in multiple aged and pathological tissues.

“The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,” Conboy said. “Dosage is going to be the key to rejuvenating the stem cell environment.”

Other co-authors of the paper are former graduate student Hanadie Yousef, now at Stanford University; and Michael Conboy, Adam Morgenthaler, Christina Schlesinger, Lukasz Bugaj, Preeti Paliwal and Christopher Greer of UC Berkeley’s bioengineering department and QB3.

The work was supported by grants from the National Institutes of Health, California Institute for Regenerative Medicine and a Rogers Family Foundation Bridging-the-Gap Award.

View UC Berkeley article

CATEGORY: NewsComments Off

FDA greenlights clinical trial of treatment for blinding disease

Novel retinitis pigmentosa therapy created by UC Irvine stem cell researchers.

UC Irvine professor Henry Klassen is using stem cells to cure retinitis pigmentosa. (Photo by Steve Zylius, UC Irvine)

A first-of-its-kind stem cell-based treatment for retinitis pigmentosa developed by UC Irvine’s Dr. Henry Klassen, Dr. Jing Yang and colleagues has received consent from the U.S. Food & Drug Administration for use in a clinical trial.

A startup co-founded by Klassen and Yang to commercialize the therapy, jCyte Inc., will administer the trial – the first to be held at UCI to test a remedy created by UCI stem cell researchers. The investigational treatment is intended to preserve vision by intervening at a time when degenerating photoreceptors (rods and cones) can be protected and potentially reactivated.

“This milestone is a very important one for our project,” said Klassen, an associate professor of ophthalmology affiliated with UCI’s Sue & Bill Gross Stem Cell Research Center and Gavin Herbert Eye Institute. “It signals a turning point, marking the beginning of the clinical phase of development, and we are all very excited about this progress.”

By midyear, the phase one/two study will begin enrolling up to 16 patients at UCI and a possible second site. The primary purpose of the trial is to determine the safety of a single injection of retinal progenitor cells into the eyes of patients with advanced retinitis pigmentosa. But the effect on ocular function also will be assessed.

Stem cell therapy offers a new and promising approach to devastating blinding diseases such as RP, for which there is no current treatment. The initiation of this clinical trial represents the culmination of a research project stretching back more than a decade – a project, according to Klassen, accelerated by support from the state’s stem cell agency, the California Institute for Regenerative Medicine, which was created when voters passed Proposition 71 in 2004.

“Without the backing of CIRM and the people of California, we would have never made it this far this quickly,” Klassen said. “To the patients and their families who have been waiting all these years, I am delighted to finally be taking our research out of the lab and into the clinic.”

CIRM has granted the team $21 million to date for the project. While the funding is extremely important, Klassen stressed that the agency also tutors and guides its grantees in the many aspects of translational development and that this partnership grows closer during the later preclinical phase, where much is at stake.

“One of CIRM’s goals is to provide the support that promising therapies need to progress and ultimately get into clinical trials with patients,” said Jonathan Thomas, Ph.D., J.D., chair of the agency’s governing board. “RP affects about 1.5 million people worldwide and is the leading cause of inherited blindness in the developed world. Having an effective treatment for it would transform people’s lives in extraordinary ways.”

Sidney Golub, director of UCI’s Sue & Bill Gross Stem Cell Research Center, added: “We are thrilled that this trial is on the verge of implementation. It represents everything that we are trying to accomplish in the UCI stem cell program, in that it is innovative and targets an important unmet medical need. We will support this exciting program in all ways we can.”

The Gavin Herbert Eye Institute at UCIwill participate in the trial, which is awaiting UCI institutional review board approval. The University of California has a patent pending on this technology. The startup jCyte has licensed rights to it from the university.

View original article

Related link:
CIRM-funded therapy for disease that attacks vision gets go ahead for clinical trial

CATEGORY: NewsComments Off

How stem cells grow depends on what they grow up in

Using mathematical model, researchers devise optimal human stem cell culture.

By Scott LaFee, UC San Diego

Human pluripotent stem cells (hPSCs) possess the ability to grow into almost any kind of cell, which has made them dynamic tools for studying early human development and disease, but much depends upon what they grow up in.

Writing in the May 4 online issue of the journal Scientific Reports, researchers at the UC San Diego School of Medicine used a powerful statistical tool called “design of experiments” or DOE to determine the optimal cell culture formula to grow and produce hPSCs.

“Currently, there are different culture methods and media that are not optimized or even chemically defined. There are several factors that may affect the growth of stem cells based on batch-to-batch media variation,” said Alysson Muotri, Ph.D., associate professor in the UC San Diego departments of pediatrics and cellular and molecular medicine. “This affects science in many ways. For example, it slows down progress because conditions may not be pristine. It also makes it difficult for other labs to validate data because the media they use will likely not be the same as in the original experiments.”

Muotri and colleagues used DOE to measure two critical growth factors used in hPSC media: basic fibroblast growth factor (bFGF) and neuregulin-1 beta 1 (NRG-1 beta 1). DOE is often used in scientific endeavors to measure and account for variations in data, but not so much in biology, said Muotri.

“If you ask a biology student what is the ideal temperature and pH for an enzyme, he/she will try to determine the best temperature in one experiment and the best pH in another experiment. Then, the student will erroneously conclude that these represent the optimal temperature and pH,” said Muotri. “What is missing is the interaction between temperature and pH. The best working temperature may not be the most optimal pH condition. DOE takes into account positive, negative or neutral interactions between multiple factors at the same time.”

Building upon earlier work, which had analyzed hundreds of other factors in hPSC media, the researchers determined the best formulations for bFGF and NRG-1 beta 1. They noted, however, that their findings are not fixed. “If science discovers a new factor that affects hPSC proliferation, we can add it into our DOE matrix to quickly test and re-formulate the media,” said Muotri.

The researchers hope their findings will lead to a new standard for hPSC cultures. “Any lab in the world can have access to the same formulation, with no variability,” said Muotri. “We also think this method could be applied towards the development of culture conditions during differentiation of human stem cells. Ideally, we want to create transition media formulations that subtly change during cell type specialization, mimicking the human embryo.”

Muotri said his team is working with the UC San Diego Technology Transfer Office to find industry partners to assist in making the new technology accessible to all laboratories using hPSCs.

Co-authors include Paulo A. Marinho and Thanathom Chailangkarn, UCSD Department of Pediatrics/Rady Children’s Hospital-San Diego, Department of Cellular and Molecular Medicine and UCSD Stem Cell Program.

Funding for this research came, in part, from the California Institute for Regenerative Medicine and the National Institutes of Health (1-DP2-OD006495-1).

View original article

CATEGORY: NewsComments Off

Prenatal stem cell treatment improves mobility issues caused by spina bifida

Lower-limb paralysis associated with the birth defect may be effectively treated before birth.

Fetal surgeon Diana Farmer (front), stem cell bioengineer Aijun Wang (behind her) and their research team are testing placental stem cells as a treatment for the paralysis associated with spina bifida.

By Karen Finney, UC Davis

The lower-limb paralysis associated with spina bifida may be effectively treated before birth by combining a unique stem cell therapy with surgery, new research from UC Davis Health System has found.

The study, conducted in an animal model, was led by Diana Farmer, the fetal surgeon who helped pioneer in utero treatment for spina bifida — a congenital birth defect that occurs when the spinal cord does not close properly, leading to lifelong cognitive, urological, musculoskeletal and motor disabilities. Farmer’s chief collaborator was Aijun Wang, co-director of the UC Davis Surgical Bioengineering Laboratory.

“Prenatal surgery revolutionized spina bifida treatment by improving brain development, but it didn’t benefit motor function as much as we hoped,” said Farmer, chair of the UC Davis Department of Surgery and senior author of the study, published online today (April 24) in Stem Cells Translational Medicine.

“We now think that when it’s augmented with stem cells, fetal surgery could actually be a cure,” said Wang.

Farmer and Wang are the first to combine fetal surgery with a placental stem cell treatment to reduce the effects of spina bifida, which in children can range from barely noticeable to severe. The most common and disabling form of the disorder, called myelomeningocele, causes the spinal cord to emerge through the back, often pulling brain tissue into the spinal column and causing cerebrospinal fluid to fill the interior of the brain. Permanent shunts are required to drain the extra fluid.

Farmer was senior author of the landmark Management of Myelomeningocele Study (MOMS), which showed that prenatal surgery could improve cognitive outcomes for the 1,500 children born each year in the U.S. with spina bifida. A majority of treated children in the study, however, were unable to walk independently at 30 months of age.

For the current research, lambs with myelomeningocele received fetal surgery to return exposed tissue to the spinal canal. Human placenta-derived mesenchymal stromal cells (PMSCs) — known for their neuroprotective qualities — were preserved in hydrogel and applied to the site of the lesion. A scaffold was placed on top to hold the hydrogel in place, followed by surgical closures to complete the repair.

Six animals that received the stem cell treatment were able to walk without noticeable disability within a few hours following birth, while six control animals that received just the hydrogel and scaffold were unable to stand.

“We have taken a very important step in expanding what MOMS started,” said Wang. “Next we need to confirm the safety of the approach and determine optimal dosing.”

Farmer and Wang will continue their efforts with funding from the California Institute for Regenerative Medicine. With additional evaluation and FDA approval, the new therapy could be tested in human clinical trials.

“Fetal surgery provided hope that most children with spina bifida would be able to live without shunts,” Farmer said. “Now, we need to complete that process and find out if they can also live without wheelchairs.”

Additional authors were Erin Brown, Lee Lankford, Benjamin Keller, Christopher Pivetti and Nicole Sitkin of UC Davis, and Michael Beattie and Jacqueline Bresnahan of UC San Francisco. Their study — titled “Placental Mesenchymal Stromal Cells Rescue Ambulation in Ovine Myelomeningocele” — was funded by the UC Davis Department of Surgery. It is available online at http://stemcellstm.alphamedpress.org/content/early/recent.

View original article

CATEGORY: NewsComments Off

Researchers issued patent for method that helps validate stem cells created in lab

Using tumor rejection antigen to ID stem cells could help ensure studies are accurate.

Cell colony with induced pluripotent stem cells stained in red using the tumor rejection antigen, or TRA, method. (Image by UCLA Broad Stem Cell Research Center)

By Mirabai Vogt-James, UCLA

Two UCLA stem cell researchers have received a patent for their method of verifying that stem cells created in a lab using adult donor cells have potentially reached a pluripotent state, which means they are capable of turning into any other cell in the body.

The patent was issued to William Lowry and Kathrin Plath of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research for their work using a tumor rejection antigen, or TRA, to identify stem cells that have pluripotent characteristics.

Induced pluripotent stem cells 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. But prior to the use of the TRA method, the process of picking pluripotent stem cells out of the other cellular matter contained in the petri dish was a lot like trying to find a needle in a haystack.

“Using the TRA method is an important validation step to ensure that the target cells have potentially been reprogrammed to a pluripotent state,” said Plath, professor of biological chemistry at UCLA. “This accurate identification of reprogrammed cells is critical as we conduct research to better understand the viability of pluripotent stem cells for therapeutic treatments for human disease.”

Validating the pluripotent state of stem cells has become a critical step in ensuring stem cell research studies are accurate.

Read the full news release.

CATEGORY: NewsComments Off

‘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.

View original article

CATEGORY: NewsComments Off

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.

For more information:

Related links:

CATEGORY: NewsComments Off

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.

View original article

CATEGORY: NewsComments Off

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.

View original article

Related link:
Discovery opens the door to a potential ‘molecular fountain of youth’

CATEGORY: NewsComments Off