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)


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Engineered human stem cells destroy HIV infected cells

A group at the University of California, Los Angeles AIDS Institute has manipulated human blood-forming stem cells to fight HIV infected cells. The technique could conceivably be used to help the body fight any number of viral infections, the authors say.

The researchers started with blood-forming stem cells normally found in the bone marrow. These cells form all the cells of the human blood system including immune and red blood cells. They then inserted a gene from an immune cell of an HIV-infected individual. That protein can recognize the HIV virus and would ordinarily guide the person’s immune system to attack infected cells. In an HIV-infected person so few of those infection-fighting cells exist that the immune system can’t do its job. 

The idea was that blood-forming stem cells carrying that HIV-targeting protein would mature into an immune system primed to recognize and destroy HIV-infected cells.

To test their idea, the authors inserted the engineered stem cells into mice. These mice also had transplanted into them a human thymus, the organ that is responsible for making a population of infection-fighting cells called T cells. (The human T cells can’t mature properly in the mouse thymus. By implanting the mouse with a human thymus the researchers mimicked how the cells might behave in a human.) As they hoped, the blood-forming stem cells produced  human T cells that were able to kill HIV-infected cells.

The authors called this study a proof-of-principle, saying that by inserting different proteins into the blood-forming stem cells they could direct the immune system to attack Hepatitis, herpes or human papillomavirus.

A press release by UCLA quotes Jerome Zack, an author on the paper and CIRM grantee, as saying:

"This approach could be used to combat a variety of chronic viral diseases. It's like a genetic vaccine."

PLoS ONE, December 7, 2009
CIRM funding: Jerome Zack (RC1-00149)

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400th CIRM-funded paper clarifies link between gene variant and Alzheimer's

The 400th paper published with CIRM funding also marks the five-year anniversary of the first CIRM board meeting (the actual date was December 17, 2004). The paper, by researchers at the Gladstone Institute and the University of California, San Francisco, illustrates how far the field has come in the five years since the organization’s inception, and in the three years since the organization has been funding research.

The paper reveals why people with a particular gene variant called ApoE4 are more likely to develop Alzheimer’s disease and identifies possible drug treatments to block the effects of that gene variant. The gene ApoE makes a protein that is involved in lipid metabolism and neuronal repair and remodeling. As with all genes, people can inherit different variants, and each variant makes a slightly different protein.

People with the variant called ApoE4 have long been known to be at higher risk of developing Alzheimer’s disease, but nobody has known why. In a press release by the Gladstone Institute, senior author Yadong Huang said:

“Our findings suggest that apoE4 inhibits the development of newborn neurons by impairing the GABAergic signaling pathway and that boosting this pathway with drugs may be of therapeutic benefit. It might allow us to encourage the development of new neurons from stem cells to replace those lost in apoE4 carriers with AD.”

The ApoE4 protein prevents the brain’s pool of stem cells from replacing cells lost to Alzheimer’s disease. Understanding this basic biology could result in a new drug that blocks the inhibitory effects of ApoE4 and acts as a call to action to the brain’s stem cells. (The image shows the brains of mice, with ApoE in green and neural stem cells in red.)

CIRM was voted into existence by 59% of California voters eager for new disease therapies. CIRM has only been funding research for three years due to a lawsuit. In that short time several CIRM grantees have made discoveries about how Alzheimer’s develops, how stem cells might be used in a future therapy, and now how drugs might be used to treat the disease in a particular group of people. Each of these is a step toward fulfilling the hope of Calfornians who voted for Proposition 71.

Typical of most CIRM-funded papers, at least one of the authors on the 400th paper is on a training grant. These graduate students, postdocs and clinical fellows working on stem cell projects contributed to 69% of all papers published with CIRM funding. Their work spans the most basic biology – work that is needed in order to understand the basic functionality if stem cells – and projects that are moving those basic discoveries toward the therapies.

The incredible productivity of these grantees is not a surprise. The CIRM Governing Board recognized the importance of pulling students into stem cell projects and funded the first training grants in April 2006 with Bond Anticipation Notes before the agency’s legal battles had completed.

Of the 400 published papers, almost a quarter were in high profile publications such as Science, Nature, and the Cell journals.

Cell Stem Cell, December 4, 2009 PMID: 19951691
CIRM funding: Yudong Huang (RN2-00952), Gang Li T2-00003 (T2-00003)

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Lever found for switch to re-grow your tail—if you’re a fish

Embryonic stem cells stand poised to grow into various tissues, but are held in check by chemical switches that keep the necessary genes turned off. Researchers at the Salk Institute for Biological Studies found that genes responsible for limb regeneration – in this case the snipped tail of a zebrafish – are held in a similarly poised state by those same chemical switches.

It turns out that both embryonic stem cells and regenerative cells of the fish tail require enzymes called demethylases to release them from the poised state. In fact, zebrafish missing one of those enzymes are unable to re-grow their tail, something they routinely do in about a week.

A press release from the Salk Institute quotes first author Scott Stewart, postdoctoral scholar and CIRM training grant recipient, as saying:

“This is the first real molecular insight into what is happening during fin regeneration. Until now, how amputation is translated into gene activation has been like magic.”

While this sort of regeneration is common in fish and certain amphibians, it is unheard of in mammals. The Salk team plans to use this new finding to ask more specific questions about how we might be able to cross the barrier and induce limb regeneration in mammals.

The Salk Institute press release quotes the senior author Juan Carlos Izpisúa Belmonte, as saying:

“This finding will help us to ask more specific questions about mammalian limb regeneration: Are the same genes involved when we amputate a mammalian limb? If not, what would happen if we turned them on?”

 Proceedings of the National Academy of Science: November 24, 2009
CIRM funding: Scott Stewart (T3-00007-1)

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Embryonic stem cells repair radiation damage in mice

Radiation can effectively destroy brain tumor cells – but at a cost. While killing the tumor cells the treatment also damages normal cells in portions of the brain involved in learning and memory, leaving people with varying levels of impairment. New work by researchers at the University of California, Irvine suggests that human embryonic stem cells are able to ameliorate radiation-induced normal tissue damage.

The group, led by CIRM SEED grantee Charles Limoli, irradiated the heads of rats then transplanted human embryonic stem cells into the brain. In a memory test four months after the radiation, transplanted rats performed as well as rats that had never been irradiated. Rats that received radiation but no transplanted stem cells showed a significant decline in learning and memory.

The transplanted cells had migrated through the brain and matured into a variety of brain cells. The cells did not form any tumors (at least by 4 months) – something scientists are careful to watch for in transplanted stem cells.

In a press release by UCI, Limoli said:

"With further research, stem cells may one day be used to manage a variety of adverse conditions associated with radiotherapy."

Proceedings of the National Academy of Science: November 10, 2009
CIRM funding: Charles Limoli (RS1-00413-1), Peter Donovan (RC1-00110-1)

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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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