Fly stem cells give insights into aging and longevity

Yesterday brought news about stem cells in older people. Today, there's news by CIRM grantees about how a single gene alteration in a stem cell can help keep an entire organ more youthful -- at least in flies.

The work was by a team of researchers at the University of California, Los Angeles, the Salk Institute for Biological Studies and the University of California, San Diego. It all started with a long-known observation: cutting calories in many laboratory animals can also dramatically extend the animal's life. This is true in common lab animals such as flies, worms, and mice, and also holds true in primates.

In addition to living longer, those hungry, long-lived animals have more of the energy-producing cellular structures called mitochondria. The researchers were curious if simply boosting the number of mitochondria without all that painful hunger would work the same trick. One known way of boosting mitochondria is to rev up a protein called PGC-1.

A press release from Salk describes the work of associate professor Leanne Jones' work like this:

"This chain of connections between the mitochondria and longevity inspired Jones and her colleague to investigate what happens when the PGC-1 gene is forced into overdrive. To do this, they used genetic engineering techniques to boost the activity of the fruit fly equivalent of the PGC-1 gene. The flies (known as Drosophila melanogaster) have a short lifespan, allowing the scientists to study aging and longevity in ways that aren't as feasible in longer-lived organisms such as mice or human."

The researchers specifically bumped up the PGC-1 gene in stem cells that line the fly intestine. They found two things: 1) those fly intestine stem cells had more mitochondria, and 2) the flies lived a lot longer than their unaltered lab-mates. All that, with no starvation.

Here, I should pause to say that if you think your intestine is so different from a fly's you'd be wrong. Their intestine is lined with stem cells not unlike our own, and those cells function in a very similar way using similar genes. That's not to say that all research in flies directly translates to humans, but it is a pretty good model for testing out ideas.

Jones, who has a New Faculty award from CIRM, had this to say in the press release about the findings:

"Slowing the aging of a single, important organ - in this case the intestine - could have a dramatic effect on overall health and longevity," Jones says. "In a disease that affects multiple tissues, for instance, you might focus on keeping one organ healthy, and to do that you might be able to utilize PGC-1."

This research is in the very preliminary stages and is far from being ready for an human use. However, it's this kind of basic discovery that continuously fuels new ideas for human therapies.

CIRM Funding: Leanne Jones (RN1-00544-1)
Cell Metabolism, November 1, 2011

- A.A.

Tissue engineering produces small intestine, possible help for pre-term infants

CIRM grantees at Children's Hospital Los Angeles and the University of Southern California have succeeded in growing normal-looking small intestines in mice.

In a press release, the senior author Tracy Grikscheit said:

“The small intestine is an exquisitely regenerative organ.  The cells are constantly being lost and replaced over the course of our entire lives," she explained. "Why not harness that regenerative capacity to benefit these children?”

The group took a small sample of small intestine from mice and placed them on a biodegradable scaffolding inside the abdomen of another mouse. That scaffolding basically gave the cells something to grow on that would mimic the shape of a normal intestine. What they found is that the transplanted cells were able to form all the cell types and structures that are normally part of the small intestine.

The paper was published in the July issue of Tissue Engineering.

The press release mentions the eventual hope of using the technique to help children with intestinal failure. Babies born pre-term are at risk for intestinal damage called necrotizing enterocolitis (NEC), which occurs when the intestine is injured.

Tissue Engineering, July 2011
CIRM Funding: Tracy Grikscheit (RN2-00946), Frederic Sala (TG2-01168)

A welcome voice in stem cell communication - a new podcast launches

CIRM grantee Paul Knoepfler at UC Davis has been blogging about stem cell science for a while now. He recently expanded his outreach to include a regular podcast. It's worth checking out. He's listing the most recent podcast at the top of his main blog page: http://www.ipscell.com/ .

Knoepfler includes some science, some policy, and a nice comment on the value of CIRM's funding in advancing stem cell science. As he admits, he's not exactly unbiased. He has a New Faculty II award from CIRM and is at an institution with a shared lab and major facility funded in part by CIRM. Still, we think he's right when he says:

"In a state where there s so much going wrong Californian's should be proud of their foresight in creating CIRM and in all that CIRM has already accomplished. CIRM is one of the things in ca that is actually going really well and we should be happy about it."

There are a few groups competing for the public's attention on stem cell topics. Those opposed to stem cell science have a few blogs, which they promote heavily. These generally tout advances with adult stem cells. Many of those advances are very hopeful, and we tout them too, but telling one side of the story doesn't ever give a complete picture of the field.

Several organizations such as CIRM, the Canadian Stem Cell Network and the Australian Stem Cell Centre also have blogs that promote stem cell science and attempt to put recent scientific advances into context. However, to my knowledge Knoepfler is the only stem cell scientist attempting to reach the public online. I look forward to hearing more podcasts from Knoepfler, and wish him much success in providing accurate information about stem cell research at a time when it is so clearly needed.

A.A.

Origin of lung mucus glands found, insights for cystic fibrosis, asthma

Last week's big news at CIRM was the election of Jonathan Thomas as the new governing board chair, as we announced late Wednesday night. He will be replacing Robert Klein, who has served the agency since its inception in 2004. Not that anyone can replace Klein, exactly, but Thomas seems eager to step in and start leading the agency.

While many of us at CIRM were distracted by our board meeting and subsequent leadership change, CIRM grantees kept on doing science, as evidenced by a paper in Stem Cells which came out today.

Scientists with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have fund the stem cell that makes all the cells of the mucus glands in the airways of the lungs. By and large, scientists assume that most tissues of the body arise from a pool of tissue-specific stem cells. These stem cells have been identified in the blood system, brain, muscle, skin and a variety of other tissues. Once found, scientists can begin developing ways of harnessing those cells to treat disease.

Until assistant professor Brigitte Gomperts and postdoctoral scholar Ahmed Hegab published this work, nobody knew the origin of the mucus cells in the airway. These cells play a critical role in protecting the body from infectious agents or toxins in the environment. A UCLA press release quotes Gomperts:

“We’re very excited that we found this population of cells because it will allow us to study mechanisms of diseases of the upper airway. For example, there currently are no treatments for excess mucus production, which we see in cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). But if we can understand the mechanisms of how these stem cells repair the mucus glands, then we may be able to find a way to put the brakes on the system and prevent mucus over production.”

I often read about people who claim that adult stem cells are as effective at treating disease as embryonic stem cells. What people seem not to understand is that there is no one adult stem cell. Stem cells of the blood system are fantastic, but they don't repair muscle, skin, brain, or, in this case, mucus glands. Finding these tissue-specific stem cells is the necessary first step to to developing new therapies based on these cells.

Stem Cells, June 27, 2011
CIRM Funding: Brigitte Gomperts (RN2-00904-1)

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On stem cells, aging and hopes for spryer golden years

Last week my three year old scraped up the entire left side of his face. Today, there's barely a trace of the injury. That's the glory of three year old skin, or more precisely, the glory of three year old stem cells.

Erin Allday at the San Francisco Chronicle had a story last week about the issue of aging stem cells featuring several CIRM grantees who are, like me, curious about why stem cells heal damage more slowly as we age. Her story includes Thomas Rando of Stanford University, whose work I wrote about several years ago. What I found fascinating then, and what still isn't understood, is why a stem cell grows less able to repair damage over time. Rando and his former postdoctoral fellow Irina Conboy (now at University of California, Berkeley) have found that in older muscle, the stem cells are still able to respond, but the signals themselves may not be as strong. The stem cells are there, they just don't hear damaged muscle's cry for help.

Allday quotes Rando, who is director of the Glenn Laboratories for the Biology of Aging at Stanford:

“I don’t necessarily see it as a way of reversing Alzheimer’s or making people live to 200 years old, but there’s this dormant potential that can be unleashed that can profoundly affect the way stem cells repair tissues.”

Allday also quotes Irina Conboy, who spoke at last week's annual meeting of the International Society for Stem Cell Research in Toronto:

Like physicists trying to find the unified theory of everything, we’re trying to find the unified theory of all these bad things that happen with aging. I think they all stem from a lack of stem cell responses.

Conboy has a New Faculty Award from CIRM to learn more about how stem cells age.

Nobody is arguing that studying stem cells will uncover the fountain of youth (at least, CIRM scientists aren't). Instead, CIRM President Alan Trounson said that by understanding how and why our body's stem cells age scientists could learn how to keep those stem cells more lively during a person's golden years. We wouldn't live longer, maybe, but as long as we're alive it would be nice to heal more effectively or resist disease. Just having bones heal more quickly could significantly reduce health care costs for the elderly.

“With aging, there are a lot of systems that start to become less efficient or break down or be more inclined to diseases. We may work out ways to provide stem cells that would enable people to remain vigorous.”

Remaining vigorous sounds pretty good to me, even if I don't ever again heal with the speed of a three year old.

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CIRM grantee Robert Blelloch wins ISSCR Outstanding Young Investigator Award

CIRM grantee Robert Blelloch of the University of California, San Francisco won the 2011 Outstanding Young Investigator Award from the International Society for Stem Cell Research. The society's annual meeting is taking place now in Toronto.

Blelloch presented his research June 15 at 6pm and will participate in a press briefing at noon June 16. His work focuses on the role of small molecules called microRNAs and their role in stem cell biology and cancer.

Jennifer O'Brien described Blelloch's work in a press release from UCSF:

During the last few years, Blelloch’s team has reported several key findings. In 2008, they reported that microRNAs promote self renewal of embryonic stem cells in mice (Nature Genetics, 2008). In 2009, they showed that when those same microRNAs were inserted into adult cells the cells de-differentiated back into embryonic stem cells (Nature Biotechnology, 2009). In 2010, they inserted a microRNA into embryonic stem cells and promoted differentiation, but determined that the microRNA had to compete with microRNAs that promote embryonic stem cell self-renewal (Nature, 2010). This year, his laboratory has been looking at microRNAs as a potential tool to systematically dissect the molecular pathways that regulate cell fate transitions, including dedifferentiation of adult cells to create induced pluripotent stem cells (Nature Biotechnology, 2011).

“People have come to realize microRNAs are remarkably powerful,” said Blelloch, associate professor in the Departments of Urology, Obstetrics, Gynecology and Reproductive Sciences and Pathology and a member of the Helen Diller Family Comprehensive Cancer Center.

Using microRNAs for therapeutic purposes has great potential , he said. “They could be used either to induce adult cells to de-differentiate to embryonic stem cells, which could be expanded, manipulated and returned to a patient, or to promote differentiation of embryonic stem cells to produce tissues that would remain integrated in the body once re-introduced.” They also could be used to target cancers, and they attract interest from biotechnology companies.

Blelloch has a SEED Award and a New Faculty II Award, both looking at the role of microRNAs in embryonic stem cell biology. Not to blow our own horn, but CIRM does know how to pick high quality research. Last year Stanford's Joanna Wysocka won the same award. She has a SEED Award and a New Faculty I Award from CIRM.

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Blood from stem cells?

Blood has been among the most sought after and hardest to achieve tissue that CIRM grantees are attempting to derive from embryonic stem cells. It's an obvious target. The medical system needs a constant influx of blood, which comes entirely from volunteer donors. Creating that blood in an unlimited supply from human embryonic stem cells would significantly ease concerns about blood shortages at hospitals. We blogged about a Los Angeles Times story last January that discussed the value of this type of work.

The National Blood Data Resource Center has this to say about how much blood was used in 2001:

U.S. hospitals transfused nearly 14 million units of whole blood and red blood cells to 4.9 million patients in 2001 - that's an average of 38,000 units of blood needed on any given day.

Given those needs, the findings in a Nature paper by CIRM grantee David Traver at the University of California, San Diego could prove helpful. He and his team have discovered a gene called Wnt16 that, in the lab animal zebrafish, is key to the animal eventually developing a pool of hematopoietic stem cells, which are the source of all blood in the body.

In a press release from UCSD Traver said:

“What we need is the ability to generate self-renewing [human embryonic stem cells] from patients for treatments. But accomplishing this goal means first understanding the mechanisms involved in creating HSCs during embryonic development.”

Traver's work follow that of another CIRM grantee Inder Verma of the Salk Institute, who last month published a protocol for creating blood-forming progenitor cells from human embryonic stem cells and reprogrammed iPS cells. Discussing this work in his monthly stem cell research update, CIRM President Alan Trounson wrote:

Many more cancer and blood disorder patients could benefit from stem cell transplants if large numbers of blood forming stem cells could be grown in the laboratory. Because mature hematopoietic stem cells (HSCs) don’t expand well in culture, researchers have been trying to grow these cells from pluripotent stem cells, both embryonic stem cells and reprogrammed iPS cells. Most of these attempts have generated very low numbers of bone marrow colonizing blood precursors, and none have shown robust generation of transplantable HSCs. Now, Verma’s team has shown that with five iPS cells lines and two embryonic lines that they can efficiently generate precursors and progenitors of HSCs.

This work brings up another point often made by CIRM grantee Paul Knoepfler at the University of California, Davis. In his blog and in the Sacramento Bee Knoepfler has argued that supporting stem cell research is a matter of national security. Soldiers wounded on the battlefield need a source of blood for transfusions. Knoepfler wrote in his Sacramento Bee Op-Ed:

I hope that in the future stem cell research can perhaps slightly lessen the burden on our servicepeople and their families through technologies to save the lives of wounded soldiers.

Nature, June 9, 2011
CIRM funding: David Traver (RN1-00575-1)

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Skin cells to beating heart cells in just 11 days

(Comment: it appears that we already blogged about this study back in February. It's interesting work, though, so this second blog entry gets to remain.)

CIRM grantee Sheng Ding at Scripps Research Institute has converted mouse skin cells into beating heart cells. If this sounds familiar, it's because Deepak Srivastava at the Gladstone Institute for Cardiovascular Disease did something similar last year, but there are a few key differences.

• Ding worked with skin cells whereas Srivastava worked with cells from the heart.
• Srivastava used a group of heart-related factors to push the cells directly into becoming heart tissue. By contrast Ding began by directing the skin cells to become reprogrammed iPS cells, then did a quick change and drove those partially reprogrammed cells to become heart.

The biggest difference is in speed and efficiency. Ding's approach produced beating heart cells in 11-12 days as opposed to 4-5 weeks, and produced those cells in much higher numbers.

In his Nature Cell Biology paper, Ding did point out a few flaws with his approach. First, they need to figure out how to achieve the conversion using transient factors rather than with permanent genetic modifications. Because when it comes to therapies in humans, permanent changes to the DNA — especially with know cancer-causing genes — are frowned upon. They also need to test whether the beating cells can still function when transplanted and don't cause tumors.

Despite these hurdles, Ding and his team say their approach could be effective for a wide variety of cell types. The initial step of partially reprograming the cells would be universal, then it's just a matter of finding which factors push the partially naïve cells to form a new cell type.

In a press release, Scripps Research Institute quotes Ding as saying:

“This work represents a new paradigm in stem cell reprogramming. We hope it helps overcome major safety and other technical hurdles currently associated with some types of stem cell therapies.”

This latest paper is one more indication that it could be possible to switch one type of cell into another as a way of repairing tissue damage. However, as with so much in the field of stem cell biology and regenerative medicine, how that approach fits in with ongoing research using adult, embryonic or iPS cells is still anyone's guess.

CIRM funding: Sheng Ding (RN1-00536-1)
Nature Cell Biology, January 30, 2011

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Genetic regions guide embryonic stem cell development

Joanna Wysocka

Stem cell research generally doesn’t make the news unless it’s a story about diseases and cures. We push toward cures every day here at CIRM, but we also fund a lot of the less flashy science that — though it doesn’t make the daily news — we think will one day underlie many of those future cures.

A recent paper by CIRM grantee Joanna Wysocka at Stanford is one of those that sounds pretty basic but could end up as an important milestone in understanding how human embryonic stem cells form the various types of tissues in the body.

Wysocka, who was last year’s Outstanding Young Investigator at the International Society for Stem Cell Research meeting, found thousands of DNA regions, called enhancers, that control the activity of far distant genes. Of the enhancers they found, more than two thousand carried molecular tags that held the genes in a state much like swimmers at the start of a race — ready to spring to action but also held in check. As the stem cells matured into a given cell type, those tags holding the enhancers in check fell away and the gene was able to spring off the starting block.

In a Stanford press release Wysocka said:

“This is going to be an enormous resource for researchers interested in tracking cells involved in early human development. It will be very interesting to learn how these enhancers affect gene expression in each cell type.”

Having found these enhancers scientists can develop better tools for maturing embryonic stem cells or iPS cells into the desired cell type — heart cells, pancreas, skin, nerves or anything else. Right now, coaxing stem cells to become the desired cell type is a big hurdle and is not terribly efficient for some cell types. Anything that improves that process is a step toward those flashier papers about stem cells and cures.

CIRM Funding: Joanna Wysocka (RN1-00579-1)
Nature, December 15, 2010

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Stem cell research like picking stocks? We don't think so.

A story by Nick Wade in Monday’s New York Times rubbed some scientists the wrong way — and I must admit the piece was not too popular around CIRM headquarters.

Wade equated research funding with picking stocks. His idea is that a broad portfolio is bound to include some winners (he attributes this approach to the NIH and NSF) whereas attempts to only buy the big winners can produce a risky portfolio (an approach he attributes to CIRM).

Writing for the science portal Science 2.0, Michael White writes:

This is not right.* Wade goes astray in thinking of science in terms of hits and misses. Basic research is not like being at bat, with the occasional single base hit or home run being the exception in a sea of strikeouts.

Most research is simply conventional and incremental. Most of the time it's not a miss, a disaster, or a failure - it's a small, sometimes not too surprising addition to our knowledge of a subject. Most research projects and NIH grants end in success, not failure - but the successes are usually small. In fact, there probably aren't enough failures, because, unlike the venture capitalists Wade compares it to, the NIH is very unwilling to take risks in search of the spectacular winner. Funded projects are the ones almost guaranteed to work.

CIRM grantee Paul Knoepfler at UC Davis also takes objection to the piece. His point: CIRM isn’t just investing in one big thing. Three billion dollars to just fund one area of stem cell research, that would be narrow. But CIRM has funded an incredible range of research, from the most basic science to translational work, and in approaches spanning stem cell transplantation therapies to modeling disease, drug testing, and models of regeneration (the very research Wade suggests we should fund).

Knoepfler writes:

Clearly [Wade] knows very little about CIRM and about stem cell research. He makes the argument that because CIRM only funds research in 'a single field' that chances are high that Californians will lose out. First, he is wrong that CIRM only funds one field. The breadth of research funded by CIRM spans a few dozen fields from cancer biology to neurological disorders, to heart disease, diabetes, HIV/AIDS, etc. Second, Mr. Wade ignores the substantial accomplishments that CIRM has already made in just its first few years.

Where CIRM agrees with Wade’s piece is in his suggestion that we look to how animals such as zebrafish and newts naturally regenerate, and use that knowledge to improve human regeneration. Deepak Srivastava from the Gladstone Institutes, who has been looking at tissue regeneration in mouse hearts, is making tremendous progress in part through CIRM funding (here is his research summary), as is USC’s Gage Crump, studying zebrafish jaw regeneration as a model for bone regeneration (here is his research summary). 

For people interested in seeing the range of what CIRM has funded, we have this searchable list of all our funded stem cell research awards. We also have this list of our rounds of funding, explaining the role that funding plays in creating CIRM’s broad research portfolio.

A.A.

Food begets stem cells?

Drosophila intestinal stem cells (ISCs)
respond to nutrient availabilityImage:
Courtesy of Dr. Lei Wang,
Salk Institute for Biological Studies

Researchers at the Salk Institute for Biological Studies have found an intriguing connection between stem cell behavior and food. The more food, the more stem cells, and those stem cells divide more vigorously.

The researchers did their work in flies, which provide a ready laboratory for studying tissue stem cells in their natural environment. Flies have a pool of stem cells in the testes and in the intestine that are easy to monitor under different conditions and that mimic similar cells in our bone marrow, liver or muscles in their capacity to rebuild tissue.

What they found is that in flies fed a poor diet, the stem cell pool in the testes and intestines dwindled and those remaining cells divided sluggishly. Improving the flies’ diets rebuilt the stem cell pool. It appears that the protein insulin, which is present in the blood after a meal, is what signals stem cells about the presence or absence of food. The findings are published in the Nov. 4, 2010, online edition of the journal Current Biology.

In a press release, Salk writes:

"Tissues that are maintained by stem cells respond to adverse environmental conditions by reducing the overall number of stem cells, as well as the activity of those stem cells, but maintain them in such a state that they can respond quickly and effectively once the nutritional conditions become more favorable," says Leanne Jones , Ph.D., assistant professor in the Laboratory of Genetics, who led the study.

Symmetric division of male germline
stem cells (GSCs) in a Drosophila testisImage:
Courtesy of Dr. Catherine McLeod,
Salk Institutefor Biological Studies

Jones has a New Faculty Award from CIRM, although this study is not part of her grant. Salk went on to write:

Jones and her team think it likely that the link between insulin signaling and stem cell response will turn out to be important not only for nutrient deprivation but also for other situations where a body's metabolism might be altered. "One may think of how tissue homeostasis is modified in a situation when the body cannot accurately monitor or utilize available nutrients-for instance, in case of a person who is diabetic," says Jones.

They also hint that if the presence or absence of food can alter stem cell behavior, perhaps dramatic changes in diet could be incorporated into therapies.

Following on the heals of Halloween, here’s hoping chocolate turns out to be a food that brings out the best in stem cells.

A.A.

Legal wrangling slows Stanford researcher's quest for a cure

Joanna Wysocka/Stanford University

What does all the legal wrangling mean for stem cell scientists? Stanford published a profile of up-and-coming star Joanna Wysocka, who talks about her own NIH-funded research. Wysocka was awarded the Outstanding Young Investigator Award at the annual meeting of the International Society for Stem Cell Research in June and has both a SEED and a New Faculty award from CIRM. In her acceptance speech for the ISSCR award Wysocka credited her SEED award for pulling her into the field of stem cell research.

Amidst her other successes, Wysocka also received the highest of scores on an NIH grant proposal that would fund stem cell research with the promise to help children with a rare developmental disorder known as CHARGE syndrome, which leads to life-threatening complications.

That award is one of the ones that got held up in the Aug. 23 ruling that threw NIH funding of human embryonic stem cell research into a tailspin. The Stanford story says:

“I am currently funding this project largely from leftovers of my start-up funds and relatively unrestricted junior investigator awards, but we need more money to continue,” she said. While the latest ruling means that the NIH can fund grants like hers, there is uncertainty among researchers nationwide due to the unsettled state of the law.

As of September 9, the NIH can once again proceed with funding human embryonic stem cell grants, but that funding is far from settled. That uncertainty could lead to significant delays.

Although the NIH now can move forward on her grant, she’s not sure how fast it can act — and whether the next court ruling could deal another setback before that happens. She noted that the NIH committee that must give final approval for her funding met while Lamberth’s ruling was in effect, so it did not consider her grant. That committee meets only three times a year, she said, so now she may have to wait.

“The review process was disrupted — it’s not something that can change in a day,” she said. “I have no clue when my grant will get back on track.”

The stem cell researchers and people employed in their labs are disrupted by the legal back and forth, but what’s worse is the uncertainty for families of children with CHARGE syndrome who look to work like Wysocka’s with hope.

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iPS cells from women create model for muscular dystrophy, X-linked diseases

Reprogrammed skin cells showing inactivated X in red

CIRM grantees at the University of California, Los Angeles have uncovered a feature of reprogrammed iPS cells that make them uniquely excellent for understanding diseases that arise from mutations on the X chromosome.

First some background. Men inherit an X chromosome from their mother, which contains many thousands of genes, and a Y from the father, which does little except confer manhood. Women inherit one X chromosome from each parent. Those female cells overcome their genetic overabundance by shutting down, at random, one of the two X chromosomes, putting the cells at genetic par with male cells.

But the two aren’t really equal. If men inherit a mutation on an X chromosome, it is present in every cell of the body and can cause muscular dystrophy, Rett Syndrome, color-blindness and other disorders. Women who inherit a mutation on an X chromosome from one parent will only show that mutation in half their cells. The other half of the body's cells, with the non-mutated chromosome active, can generally compensate.

So what does this have to do with reprogrammed cells and disease modeling? It turns out that the process of reprogramming skin cells into embryonic-like induced pluripotent stem cells doesn’t overturn the inactivated X. Reprogramming cells from a woman’s skin sample will produce two distinct types of iPS cell lines; half with one X active, and half of with the other X active. If one of those two chromosomes carries a mutation, say, for muscular dystrophy, some of those iPS lines will also display that mutation.

In a press release from UCLA, senior author Kathrin Plath said:

“This non-random pattern of X chromosome inactivation found in iPS cell lines has critical implications for clinical applications and disease modeling and could be exploited for a unique form of gene therapy for X-linked diseases.”

In a publication in Cell Stem Cell, Plath and her colleagues report that they created iPS cell lines from a woman who had inherited one X chromosome carrying a mutation that can cause muscular dystrophy. The other X chromosome had a normal copy of the gene. Scientists can now mature both groups of cells into skeletal muscle and compare the resulting tissue as a way of understanding—and perhaps one day treating—the devastating disease.

Cell Stem Cell: September 3, 2010
CIRM funding: Sean Sherman (TG2-01169), Kathrin Plath (RN1-00564), William Lowry (RS1-00259), Jerome Zack. (RL1-00681)

Resting stem cells are cancer-prone

CIRM grantees at University of California, San Francisco, have published a Cell Stem Cell paper explaining why blood-forming stem cells accumulate cancer-causing mutations with age. Basically, they found that inactivity is genetically risky for the cells.

The blood-forming stem cells exist in the bone marrow where they divide periodically to form new cells of the blood system, including red blood cells, immune cells and platelets. When the cells are actively dividing they use a highly effective mechanism for repairing any damage to their DNA. The danger comes during the down-time. When the cells -- also called hematopoietic stem cells -- aren't dividing they use a less rigorous method for repairing DNA damage, which can be caused by radiation, drugs, or regular wear and tear.

In a press release from UCSF, the lead author Emmanuelle Passegué said:

“Our results demonstrate that quiescence is a double-edged sword, protecting hematopoetic stem cells from cellular stress but rendering them intrinsically vulnerable to mutagenesis following DNA damage.”

Passegue is associate professor of medicine (division of hematology/oncology) and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. She also received a CIRM New Faculty II Award, which funded this work.

A review that accompanies the paper says:

Because many hematopoietic disorders that stem from DNA damage accrual arise during aging, these results also stress the importance of examining DNA damage response and damage accrual during ontogeny and aging.

Cell Stem Cell, August 6, 2010
CIRM funding: Mary Mohrin (T1-00002); Emmanuelle Passegué (RN2-00934-1)

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CIRM grantee Joanna Wysocka wins Outstanding Young Investigator Award

Some happy news from this week's meeting of the International Society for Stem Cell Research held in San Francisco (co-sponsored by CIRM): CIRM grantee Joanna Wysocka won the organization's Outstanding Young Investigator Award, given out at a session on Thursday morning. Wysocka, who is assistant professor of developmental biology at Stanford University School of Medicine, has SEED and New Faculty Awards to study how cells determine their eventual fate in a developing embryo.

In her acceptance speech, Wysocka credited CIRM with directing her work toward stem cell research. After receiving her award, she discussed some of her recent work, described in a recent blog entry from Stanford:

She went on to discuss her recent work in identifying the molecular cause of a human disorder called CHARGE. She also showed how her team has since used an analytical program created by Stanford developmental biologist and computer scientist Gill Bejerano, PhD, to identify more than 2000 sites on DNA that may affect the activity of a special type of cell called a neural crest cell. 

Congratulations to Wysocka and to Stanford!

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Small DNA changes, life or death consequences

Two recent papers by CIRM grantees highlight the importance of understanding basic stem cell biology while developing new cures. Both have to do with chemical modifications to the DNA – called epigenetics.

One of the two papers shows that an epigenetic change in DNA, called methylation, changes dramatically as human embryonic stem cells mature into specific cell types; the other shows that even subtle DNA methylation differences alter the way a cell behaves.

The first paper, by Jeanne Loring at The Scripps Research Institute, working with scientists in Singapore and New York, provides detailed maps of DNA methylation over the entire 3 billion “letters” that make up our DNA. By comparing methylation patterns of human embryonic stem cells and more mature cells, the scientists tracked the large number of epigenetic changes, many of them surprises, that occur when cells differentiate.

A press release quotes first author Louise Laurent as saying:

"The data are publicly available, and we are looking forward to learning what other scientists discover from using this information for their own studies on individual genes, embryonic development, and stem cells."

The second paper, from UCLA, focuses on epigenetic differences in pancreatic cancers, showing that differences in these modifications translate to different responses to chemotherapy. This means that a few DNA modifications here or there could mean life or death.

In a press release the authors say the next step is to develop a test doctors can use to figure out which patients will respond well to standard chemotherapy and which need an alternative treatment.

Taken together, the papers make a compelling case for how basic biology research such as understand DNA modifications can inform scientists who are actively pursuing cures.

Genome Research, February 4, 2010
CIRM funding: Jeanne Loring (RT1-1108 and TR1-01250)

Journal of Clinical Oncology, February 8, 2010
CIRM funding: Siavash Kurdistani (RN1-005505)

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Longevity gene regulates neural stem cells in mice

Researchers at the Stanford University School of Medicine have found that a gene long-known to regulate the lifespan of tiny roundworms also plays a role in regulating neural stem cells in mice.

Variations of the gene family, called FoxO, help roundworms live to an unusually ripe old age in the lab, and mutations in the FoxO3 gene have also recently been associated with long life in Japanese, German, American and Italian populations. Laboratory mice lacking FoxO3 live to about half their usual age of 30 months before dying of cancer.

The group found that in addition to dying young, adult mice lacking FoxO3 had fewer neural stem cells than normal mice of the same age. These neural stem cells normally generate new brain cells as needed, and also replenish their own population to maintain a lifetime pool of cells.

According to a press release by the Stanford University School of Medicine:

The researchers also discovered that the few stem cells found in the adult mice without FoxO3 more rapidly churned out neural cell precursors — those cells destined to become new neurons — than did the mice with normal FoxO3 levels. In fact, the brains of the mice that lacked FoxO3 were heavier than the control group, perhaps because they were burning through their pool of neural stem cells by making too many new nerve cells.

A better understanding of how neural stem cells maintain the brain as it ages could help those researchers who are developing therapies for disorders such as Alzheimer’s and Parkinson’s disease or stroke.

Cell Stem Cell: November 6, 2009
CIRM funding: Anne Brunet (RN1-00527-1)

Related Information: Stanford University School of Medicine, Brunet bio

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Old muscle stem cells experimentally returned to youth

Researchers at the University of California, Berkeley have found molecular pathways that human muscle stem cells rely on to repair damaged muscle. These pathways are active in younger people but less active in older people, explaining why muscles repair more slowly with age. The group found that younger volunteers had double the number of regenerative muscle stem cells in their thigh muscles compared to older volunteers. After two weeks in a leg cast, both groups began exercise routines to rebuild muscle. During this phase, the older volunteers had four times fewer muscle stem cells and rebuilt muscle more slowly. The researchers said that the poor response wasn’t the fault of the older stem cells. Instead, signals in the aging muscle and blood locked the stem cells in an inactive state. From their work in mice, the researchers knew that proteins present in the muscle surrounding the stem cells helped these cells respond to distress signals from the injured tissue. In the human cells, they found a protein called MAPK that interprets these distress signals and triggers the muscle stem cells to begin the repair process. Young people have high levels of MAPK and older people have low levels of MAPK, providing one explanation for the older volunteers’ poor response to exercise. In a lab dish, the group found that by artificially blocking MAPK in young muscle stem cells they could make young cells respond like older cells in a matter of days. The reverse was also true. Amplifying MAPK in older muscle stem cells in a lab dish rejuvenated the older cells. This work is an important step in verifying results from mouse stem cell aging studies in humans. The researchers hope their work could lead to therapies for muscle diseases and help older people to remain active, build stronger muscles and recover from injury.

EMBO Molecular Medicine: September 30, 2009
CIRM funding: Irina Conboy (RN1-00532-1), Morgan Carlson (T1-00007)

Related Information: Press Release, University of California, Berkeley

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Protein required to maintain full potential of stem cells

Researchers at the University of California, San Francisco have pinpointed a protein that is critical for maintaining a stem cell’s full potential to self-renew and to differentiate. Stem cells lacking the protein were impaired in their ability to divide and make identical copies of themselves, called self-renewal. These cells also lost their capacity to differentiate into key cell types, such as cardiac muscle. The protein, Chd1, acts to keep chromosome strands loosely wound, which permits widespread gene activation in the cell’s nucleus. Previous studies hypothesized that this open chromosome structure is necessary in stem cells to maintain their potential to specialize into any cell type. Additional results in this study demonstrate that Chd1 is required for efficient reprogramming of adult cells, such as skin cells, back into a pluripotent state. These new insights into Chd1 function may lead to safer, more efficient methods for growing up large numbers of embryonic stem cells and deriving specific cell types, both critical steps for successful stem cell therapeutic strategies.

Nature, July 8, 2009 (online publication)
CIRM funding: Rupa Sridharan (T1-00002), Kathrin Plath (RN1-00564-1), Miguel Ramalho-Santos (RS1-00434-1)

Related Information: press release, University of California, San Francisco

Genetic differences found between adult cell and embryonic-derived stem cells

Researchers at the University of California, Los Angeles have found genetic differences that distinguish induced pluripotent stem (iPS) cells from embryonic stem cells. These differences diminish over time, but never disappear entirely. iPS cells are created when adult cells, such as those from the skin, are reprogrammed to look and behave like embryonic stem cells. But until now, scientists didn’t know if the two types of stem cells were actually identical at a molecular level. This latest research shows that iPS and embryonic stem cells differ in which genes they have turned on or off. All early iPS cells share these genetic traits, regardless of what animal they come from, the type of adult cells the iPS cells start as, or what method was used to reprogram those adult cells. However, later cultures of iPS cells show that most, but not all, of these differences disappear over time, making later cultures of iPS cells more similar to embryonic stem cells. If scientists want to use iPS cells in medical therapies, this research will give them a better idea of how similar they are to embryonic stem cells.

Cell Stem Cell: July 2, 2009
CIRM funding: Mike Teitell (RS1-00313), Kathrin Plath (RN1-00564-1), William Lowry (RS1-00259-1, RL1-00681-1)

Related Information: Press Release, University of California, Los Angeles