Cells derived from embryonic stem cells, iPS cells appear immature

A trend over the past few years has been comparing embryonic stem cells, adult stem cells and reprogrammed adult cells (also known as iPS cells) to each other and to other cell types. The goal is to understand what the cells are, exactly, and and how they differ from each other. Eventually this information could help researchers learn which type of cell will be most effective for developing therapies, understanding diseases or drug screening.

A group of CIRM grantees at UCLA has published the latest in the unfolding story of stem cell comparisons. In their case, they didn't compare the stem cells themselves. Instead, they matured embryonic stem cells and iPS cells into the cells that eventually form neurons, cells that eventually form skin, and cells that eventually form liver. These so-called progenitor cells also exist in adult humans, where they lurk in tissues waiting to be needed to repair damage.

The scientists compared the progenitor cells to each other and to equivalent cells taken from adult tissue as well as to developing tissues. What they found is that the progenitors for nerves, skin and liver that came from embryonic or iPS cells had a lot in common with each other and with developing tissues. However, they had much less in common with their counterparts taken from adult tissues.

A press release from UCLA quotes William Lowry, who was senior author on the paper, which appeared in Cell Research.

“What we found, looking at gene expression, was that the cells we derived were similar to cells found in early fetal development and were functionally much more immature than cells taken from human tissue. This finding may lead to exciting new ways to study early human development, but it also may present a challenge for transplantation, because the cells you end up with are not something that’s indicative of a cell you’d find in an adult or even in a newborn baby.”

The release goes on to quote first author Michaela Patterson:

“One important reason to do this is to ensure that the cells we are creating in the Petri dish and potentially using for transplantation are truly analogous to the cells originally found in humans,” said Michaela Patterson, first author of the study and a graduate student researcher. “Ideally, they should be a similar as possible.”

…

“The roles these cells play in the fetus and the adult are inherently different,” she said. “It may be that the progeny, if transplanted into a human, would mature to the same levels as those found in the adult liver. We don’t know.”

This is the first paper we've seen comparing progenitor cells to adult or developing tissues. As with all first steps, we'll likely see more papers over the next few years refining and expanding on this team's findings and clarifying what these findings mean in terms of transplantation.

CIRM Funding: William Lowry (RS1-00259-1), Michaela Patterson (T1-00005)
Cell Research, August 16, 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)

Gene replacement in stem cells made easier

A press release about CIRM grantees at the Salk Institute for Biological Studies contains what might be the truest words in stem cell science:

In principle, genetic engineering is simple, but in practice, replacing a faulty gene with a healthy copy is anything but.

Several CIRM grantees could sum up their work in that same way. We've funded a variety of projects that all intend to replace faulty genes in stem cells with healthy ones, and then use the tricked-up stem cells to treat disease. That's how both of our HIV/AIDS disease teams hope to conquer HIV infection and also underlies our sickle cell disease and epidermolysis bullosa teams. (A list of disease teams with links to their research summaries is available here.)

The Salk researchers have published a paper in Cell Stem Cell describing a new way of replacing a gene with a therapeutic version. As a model, they used stem cells they had reprogrammed from a person with a genetic premature aging condition called Hutchinson-Gilford progeria. That condition is caused by a mutation in a gene called Lamin A. They used the technique to replace the defective Lamin A in the reprogrammed stem cells with a healthy copy of the gene. According to postdoctoral researcher and co-first author Guang-Hui Liu:

"The process was remarkably efficient and we couldn't detect any undesired off-target effects such genomic instability or epigenetic abnormalities," says Liu. "What's more, it allowed us to show that we can correct multiple mutations spanning large genomic regions."

The group also showed that their technique worked in mesenchymal stem cells, which are a form of tissue-specific stem cells many groups are also using to develop therapies.

The issue of being able to swap out defective genes is just one of many hurdles for scientists developing stem cell-based therapies. These behind-the-scenes issues rarely make the newspapers and remain largely invisible to the people who are waiting to see those future therapies, but are an active area of research for CIRM grantees. Hopefully work like this will help eliminate those hurdles and speed the path to the clinic.

Cell Stem Cell, May 19, 2011
CIRM Funding: Jeanne Loring (TR1-01250), Guang-Hui Liu (TG2-01158)

A.A.

How a stem cell forms a neuron

CIRM grantees at Sanford-Burnham have published another paper using an embryonic stem cell model to understand one of the earliest steps in human nervous system development. (We've blogged about their work before here.)

The group led by Alexey Terskikh has been trying to understand how a group of cells called the neural crest form nerves, skin, bone and muscle. This process has been somewhat mysterious because it happens at such an early stage in development. Scientists can't exactly peer into a woman's womb to see the process unfold.

That's where embryonic stem cells come in. These cells can form all cell types in the body, including neural crest. On their blog, Sanford-Burnham quotes first author on the May 5 Cell Stem Cell study Flavio Cimadamore:

“Neural crest cells are notoriously difficult to study in humans because of their very early and transient nature – a woman is usually not even yet aware of her pregnancy when they start to migrate and differentiate. So here we took advantage of an embryonic stem cell-based model of human neural crest previously developed in our lab to get a better understanding of the molecular pathways that control the differentiation potential of such cells in humans.”

In the current work, the team found that neural crest cells with a gene called SOX2 turned on can go on to form neurons. Those without it can't. That's critical information for people who are trying to understand diseases that arise from neural crest cells that go awry during development. Microphthalmia and CHARGE syndrome are two rare but debilitating childhood diseases that could benefit from knowing more about how the neural crest normally develops.

In the blog entry, Terskikh said:

"We hope this finding will be useful to researchers studying neural crest development and stem cell differentiation.”

CIRM funding: Alexey Turskikh (RS1-004661); Flavio Cimadamore (TG2-01162)
Cell Stem Cell, May 5

A.A.

Genes at the heart of heart deformities found through stem cell studies

CIRM grantees at The Gladstone Institutes have, over the past few years, been hard at work learning about the origins of heart deformities by studying how stem cells mature into heart tissue.

What they've learned is that small relatives of DNA, called micro-RNAs, help control when and how cells mature into heart tissue (blogged about here and here) or blood vessels (blogged about here). In recent work out of the lab of Deepak Srivastava, they also discovered three genes are activated by a key micro-RNA whose absence can lead to heart deformities. That work is published in the April 17 Developmental Cell.

The work was in fruit flies, but many basic discoveries in fruit flies directly translate to humans.

Isabelle King, who works with Srivastava at the Gladstone Institutes and led the study, said discovering those genes could help scientists understand and treat cases where the heart failed to form properly in development. A press release from Gladstone quotes King:

“In the fetal heart, subtle changes in gene dosage and timing can yield heart defects in children.”

This work is a great example of how basic stem cell research can lead to new areas to explore for disease therapies. People often think of stem cell therapies as exclusively transplantation therapies in which stem cells and their derivatives are transplanted into a diseased organ to restore function. We do fund scientists trying to do just that, but we also fund basic stem cell scientists who are discovering how diseases arise, and the genes responsible. These discoveries made possible by studying stem cells could lead to new drugs or other interventions that have nothing to do with transplantation.

On the topic of basic research, we'll be funding our third round of Basic Biology Awards at our governing board meeting next week (here are review summaries of those applications). These awards are intended to foster the kinds of basic stem cell and disease discoveries that keep new ideas — and eventual cures — flowing.


Developmental Cell, April 17, 2011
CIRM funding: Deepak Srivastava (RC1-00142); Li Quan (TG2-01160)

From stem cells to schizophrenia in a dish

Kristen Brennand

CIRM grantee Fred Gage at The Salk Institute for Biological Studies and his lab are creating a veritable cellular hospital of disease conditions playing out in laboratory dishes. What they learn from these diseases-in-miniature could lead to new ways of creating and screening drugs to treat the disorder.

In 2008, he matured embryonic stem cells into the type of nerve cells damaged in ALS. This study led to insights in how the damage occurs and could provide a way of screening new drugs. Then in November of 2010, Gage and his colleagues published a paper in which they reprogrammed skin cells from people with a genetic form of autism spectrum disorders. They then matured those iPS cells into neurons that they could study in the lab.

Now, Gage and his team have published a paper in Nature in which they pulled off a similar feat, this time with schizophrenia. They took skin cells from people with a genetic form of the disease and reprogrammed those cells back to an embryonic-like state. They then matured those cells into neurons — neurons that produced significantly fewer connections than is normally seen. What's more, the drug Loxapine, used to treat schizophrenia, helped restore those connections. No other frequently prescribed antipsychotic medication was able to restore those connections.

A Salk press release quotes Fred Gage, who is professor in the Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases:

"Schizophrenia exemplifies many of the research challenges posed by complex psychiatric disorders," says Gage. "Without a basic understanding of the causes and the pathophysiology of the disorder, we lack the tools to develop effective treatments or take preventive measures."

The group also found almost 600 genes whose activity was different between normal neurons and those from the schizophrenia cell. Roughly a quarter of those had been implicated in schizophrenia in the past.

The press release quoted Gage again:

"For many years, mental illness has been thought of as a social or environmental disease, and many thought that if affected people just worked through their problems, they could overcome them," says Gage. "What we are showing are real biological dysfunctions in neurons that are independent of the environment."

We produced a video of Gage discussing the role of stem cells in understanding diseases:


CIRM Funding: Kristen Brennand (T3-00007); Fred Gage (RL1-00649-1)
Nature, April 13, 2011

 - A.A.

Protein Linked to Normal Prostate Stem Cells and to Cancer

When I was the editor of a national magazine for physicians, I told my writers to do any story they found on prostate issues, with our overwhelming male audience then, I knew those stories would get high readership scores. My readers back then would have loved today’s news out of UCLA. The team there, led by CIRM grantee Owen Witte, found that the inhibition of a certain protein slowed the growth of an aggressive form of prostate cancer in animal models.

Scientifically, though the immediate excitement is over the double life this protein leads normally in the prostate. It regulates self-renewal of normal prostate stem cells needed to repair any injured cells. But it also aids the transformation of healthy cells into prostate cancer cells. The protein, called Bmi-1, has been associated with higher grade cancers and is predictive of poor prognosis. A UCLA press release quotes Witte as saying:

“We conclude by these results that Bmi-1 is a crucial regulator of self-renewal in adult prostate cells and plays important roles in prostate cancer initiation and progression. It was encouraging to see that inhibiting this protein slows the growth of even a very aggressive prostate cancer, because that could give us new ways to attack this disease.”

You can view a video about attempts to attack cancer stem cells here:



Cell Stem Cell, December 3, 2010
CIRM funding: Rita U. Lukacs (T1-00005, TG2-01169)

D.G.

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)

Neural stem cells help mice with chronic spinal cord injury walk again

Human neural stem cells transplanted
into mice grew into neural tissue
cells, such as oligodendrocytes.
Brian Cummings / UCI

A study published last week by CIRM grantees at UC Irvine gives a big ray of hope to people living with spinal cord injuries. Brian Cummings and Aileen Anderson showed that human neural stem cells could restore some mobility to mice with induced spinal cord injuries. According to a press release from UC Irvine:

The UCI study, led by Aileen Anderson and Brian Cummings of the Sue and Bill Gross Stem Cell Research Center, is significant because the therapy can restore mobility during the later chronic phase, the period after spinal cord injury in which inflammation has stabilized and recovery has reached a plateau. There are no drug treatments to help restore function in such cases.

Other stem cell strategies for treating spinal cord injury, including the trial by Menlo Park, CA-based Geron, focus on the period of time immediately following injury.

In this latest work, three months after the stem cell treatment the mice showed consistent improvements compared to untreated mice.

The release quotes Aileen Anderson as saying:

“This study builds on the extensive work we previously published in the acute phase of injury and offers additional hope to those who are paralyzed or have impaired motor function.”

This seems like a good time to quote Roman Reed, the namesake of the Roman Reed Spinal Cord Injury Research Act and founder of the Roman Reed Foundation: “Turning stem cells into cures.” This paper is one more step toward that goal that we all share.

PLoS ONE, August, 19, 2010
CIRM funding: Desiree Salazar (T1-00008)

A.A.

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)

A.A.

Muscle stem cells a step closer to treating muscular dystrophy

Stanford scientists have overcome one significant hurdle in developing a therapy for muscle-wasting diseases like muscular dystrophy. Until now, the muscle stem cells that stand at the ready to repair muscle damage couldn’t be grown outside the safe confines of a muscle. Once uprooted from their home and transferred to a laboratory dish, they matured into less useful progenitor cells. That’s a problem because once mature the cells no longer have the potential to be transplanted to repair muscle damaged by injury or disease.

Until Helen Blau, CIRM grantee and Stanford”s Donald E. and Delia B. Baxter Professor, had a good idea, that is. According to a Stanford press release:

The researchers wondered if the way the cells are normally grown in culture could be the problem. After all, as Blau pointed out, cells are used to rubbing shoulders comfortably with their neighbors on all sides rather than being splayed out and anchored on a rigid plastic culture dish that is 100,000-fold less elastic than true muscle.

Blau and her team grew the cells on a hydrogel that mimicked the elasticity of muscle, and voila. In the Stanford press release Blau said:

“Clearly the cells grown on the more-elastic surfaces have better survival and self-renewing properties than those grown on standard tissue culture dishes. We conducted our experiments with muscle stem cells, but I expect this will be true for other types of adult stem cells as well.”

When transplanted into mice, the cells contributed to leg muscles, showing that the cells were not only more numerous but also therapeutically useful. The group said this discovery could pave the way for scientists to grow muscle stem cells in quantities needed for transplantation therapies to treat muscular dystrophy and other muscle diseases.

Science (Express Online) July 15, 2010
CIRM funding: PM Gilbert (TG2-01159); Helen Blau (RT1-01001)

A.A.

Mysteries of stem cell migration revealed

CIRM-funded Researchers at the University of California, Irvine published an interesting paper this week that helps explain one mystery — how do transplanted stem cells go to the right place? This is an important issue for diseases such as multiple sclerosis, where transplanted stem cells would have to navigate to the damaged nerves.

In a press release, senior author Thomas Lane (shown in photo) said:

"Previously, we've seen that adult neural stem cells injected into the spinal column knew, amazingly, exactly where to go. We wanted to find what directed them to the right injury spots."

What the team found is that in mice with an induced form of MS, transplanted neural stem cells responded to signals being sent by inflammatory cells at the site of the damage. The neural stem cells responded to those signals by migrating to the right place and maturing into a type of nerve cell called an oligodendracyte, which could help heel the disease.

According to the press release, three weeks after the initial treatment, 90 percent of the cells had grown into fully formed oligodendrocytes.

Proceedings of the National Academy of Sciences, Online Edition, June 1
CIRM Funding: Kevin Carbajal and Christopher Shaumburg (T1-00008)

A.A.

Between Mice and Men, a New Type of Stem Cell

Humans and other non-human primates stand out from their fellow mammals in many ways, but notably by having one particularly oversized area of the brain. This area, the outer subventricular zone (OSVZ) feeds migrating neurons to the neocortex the seat of sensory perception, spatial reasoning, conscious thought and language. Scientists always assumed the OSVZ must have its own source of stem cells if, in the developing brain, it is supplying neurons for such a broadly vital area of the human brain. They have now found them.

Arnold Kriegstein’s team at UCSF used discarded fetal tissue to monitor cellular activity at various stages of development using a new labeling and tracking technique. They found the OSVZ to be a hub of cell proliferation. The newly found stem cell type goes through asymmetrical division producing a copy of itself and a daughter cell that is further along the path to becoming a neuron. That cell then goes through many rounds of symmetrical division producing many copies that can all then go on to become the desired neuronal cells needed in the neocortex.

A press release issued by UCSF on May 24 noted that the understanding provided by this model could shed light on many developmental brain diseases such as autism and schizophrenia. Kreigstein is quoted saying this understanding is critical:

“If we’re going to understand how these disorders develop, we have to better understand how the human and primate cerebral cortex develops.”

Understanding this developmental pathway will also inform efforts to direct neural stem cells to become the replacement cells of choice for various therapies.

D.G.

Nature, March 25 2010
CIRM Funding: Arnold Kriegstein (RC1-00346-1), Jan Lui (T1-00002)

Virus-free Technique Yields Pluripotent Stem Cells

Stem cells in fat hold intrigue for scientists because most of us have excess to spare, and the cells seem to be quite versatile. Now a team at Stanford has found a way to transform them into induced pluripotent stem (iPS) cells without using potentially dangerous viruses to carry the reprogramming genes into the cells.

This paper marks another step toward the holy grail of reprogramming, which is to find a safe, efficient way of returning adult cells to their embryonic-like state, called pluripotency. So far, most techniques are either not efficient or require inserting genes that may make the cells unsafe for therapeutic use.

The team used so-called minicircles of DNA to reprogram the cells into pluripotency. These minicircles contain just the four genes needed to transform the cells along with a fluorescence gene that allows the cells to be tracked. The minicricles are about half the size of naturally occurring plasmid rings that have been used in some other iPS transformations, and unlike integrating viruses, the minicircles do not get replicated as the cells multiply so the extra genes are lost over time, making the cells safer for therapy.

A press release from Stanford University quoted co-author Michael Longaker saying:

“This technique is not only safer, it’s relatively simple. It will be a relatively straightforward process for labs around the world to begin using this technique. We are moving toward clinically applicable regenerative medicine.”

Another co-author, Mark Kay, developed the minicircle technology a few years ago for use in gene therapy trials. This paper provides a great example of discoveries in one field impacting another, and moving them both forward.

Nature Methods, February 7, 2010
CIRM funding: Michael Longaker (RL1-00662-1); (T1-00001)

DG,

Visual Function Rescued in Rats Using Cells derived from iPS Cells

Induced pluripotent stem (iPS) cells have created excitement and head scratching ever since they were first created a little over two years ago. The excitement arises from their creation through reprogramming adult cells by manipulating their gene function, which does not require a human embryo and could potentially give a patient personalized replacement cells. But determining just how identical they are to embryonic stem cells in function has caused much consternation.

Now, a team at UC Santa Barbara and University College London has provided some pro and con information on the functionality question. Working in a rat model for age-related macular degeneration in which defects in retinal pigmented epithelial (RPE) cells lead to death of photoreceptors, they showed that RPE cells grown from iPS cells inserted into the retina prior to photoreceptor death were able to rescue the receptors and the rats retained vision.

A press release from UCSB quoted Sherry Hikita, an author on the paper saying:

“Although much work remains to be done, we believe our results underscore the potential for stem-cell based therapies in the treatment of age-related macular degeneration.”

However, the team also saw a difference between the iPS derived RPE cells and embryonic stem cell-derived RPE cells used in earlier experiments. The ESC-derived cells survived after transplant long-term, where as the iPS-derived RPE cells suffered rejection by the immune system.  This would not occur if the cells were derived from the patient receiving the therapy, but many leaders in the field have hoped that banks of iPS cells could be developed that would be less expensive than deriving new cells for each patient. Also, these banked cells could avoid transplanting cells with the same genetic mutation that caused the problem in the first place.

In the December 3 PLoS  ONE the authors speculate:

“The embryonic origin of hESC-derived RPE may reflect a more immune privileged cell type in comparison to iPS-RPE.”

To further complicate the equation, the rats in this model retained long-term visual function despite rejection of the transplanted cells suggesting the transplanted cells induced some sort of protective response for RPE cells in the surrounding tissue.

PLOS ONE, December 3, 2010

CIRM funding: David Buchholz (T3-00009)


DG

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

A.A.

Neural stem cells reverse Alzheimer's symptoms in mice

Researchers at the University of California, Irvine have reversed Alzheimer’s-like symptoms in a mouse model of the disease with injections of neural stem cells. The mice used in this study mimicked the human disease, showing learning and memory defects and accumulating both beta-amyloid plaques and tau protein tangles within the brain, the two hallmark pathologies of the disease.  Mice that received injections of mouse neural stem cells performed significantly better in memory tests than mice that received control injections. The stem cells did not replace cells lost to the disease. Instead, the injected cells secreted a protein known as brain-derived neurotrophic factor (BDNF), that helped nourish the surviving neurons, encouraging those cells to grow more fibers and form more connections. The injected cells did not reduce the plaques or tangles. Current therapies for Alzheimer’s disease can only reduce the severity of symptoms or slow progression. To date, this is only the second potential treatment shown to actually improve memory in mice with advanced plaque and tangle pathology.



Proceedings of the National Academy of Sciences, August 11, 2009
CIRM funding: Frank LaFerla (RS1-00247-1), Matthew Blurton-Jones (T1-00008)

Related Information: UCI Press Release, University of California, Irvine, LaFerla bio

E.R.

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

Molecules found that control the development of blood vessel cells

Researchers at the Gladstone Institute of Cardiovascular Disease have identified two molecules, called microRNAs, that push early heart cells to mature into the smooth muscle cells that line blood vessels. These same molecules also control when those smooth muscle cells divide to repair damage or in diseases such as cancer or atherosclerosis, which both involve unhealthy blood vessel growth. The two microRNAs, miR-145 and miR-143, are abundant in the primitive heart cells of prenatal mice, leading those cells to differentiate into various mature heart and aorta cells. After birth, both microRNAs are present mainly in smooth muscle cells, which also line the small intestine. If both microRNAs are absent, smooth muscle cells in blood vessels start multiplying. This helps heal injured blood vessels, but it can also create abnormal blood vessel growth in certain diseases. This cell proliferation can thicken blood vessels in atherosclerosis, or it can nourish tumors with blood. These findings could help scientists create smooth muscle cells from embryonic stem cells for therapeutic uses, or could lead to therapies for atherosclerosis or cancer.

Nature, July 5, 2009 (online publication)
CIRM funding: Deepak Srivastava (RC1-00142-1), Kathy Ivey (T2-00003)

Related Information: Press Release, Gladstone Institute of Cardiovascular Disease, Srivastava bio

Embryonic stem cells repair nerve damage from mutiple sclerosis in mice

Researchers at the University of California, Irvine have found that neurons derived from  embryonic stem cells were able to repair some damage in a mouse model of multiple sclerosis. In people with MS, the immune system attacks the insulation – called myelin – that covers and protects neurons of the brain and spinal cord. The transplanted cells caused a response in the animals that allowed the myelin coating to be repaired on damaged cells. In humans, repairing the myelin would likely also repair the function of those nerves, bringing back feeling and motor control in people with MS. At this time there are no therapies to repair this damage. Instead, available drugs simply slow the progression of the disease. In this early study, the transplanted neurons survived only two weeks. The authors say more work is needed to understand how the remyelination occurred and how to retain the transplanted cells.

Journal of Neuroimmunology: May 23, 2009 (online)
CIRM funding: Chris Shaumberg (T1-00008), Thomas Lane (RS1-0409)

Related Information: University of California, Irvine