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)

A.A.

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)

A.A

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)

D.G.

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)

A.A.

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

A.A.

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

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

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

Genetic Brake Key to Stem Cell Fate

Researchers at UC, Santa Barbara, have mapped the role of a genetic signal that puts the breaks on the ability of stem cells to self renew. The finding could eventually shed light on self-renewal that has run amuck as in cancer, and can immediately be put to use in managing the balancing act between self-renewal and differentiation—the process through which stem cells mature into more specific cell types such as neurons or muscle.  Specifically, they found that a microRNA, a single-stranded RNA whose function is to decrease gene expression, lowers the activity of three key genes needed for embryonic stem cell self-renewal. Conversely, they found that when this microRNA, miR-145, is lost the stem cells are prevented from differentiating into more mature cells.

Cell: April 30, 2009
CIRM funding: Na Xu (T3-00009)

Related Information: Press release, University of California, Santa Barbara

Genetic molecule enables safer method for creating iPS cells

Researchers at the University of California, San Francisco have designed a safer technique for reprogramming adult cells into a state that resembles embryonic stem cells. This method takes advantage of genetic molecules called microRNAs, which regulate the activity of genes. The original 2007 method for creating reprogrammed cells, called induced pluripotent stem (iPS) cells, relied on inserting four genes, some potentially tumor-causing, into the DNA of an adult cell such as a skin cell. Since then, researchers have whittled the number of genes down to two, and in one case generated iPS cells with only chemicals. However, the process is often inefficient. In this study, the researchers substituted one of the four genes with a microRNA molecule and obtained iPS cells at high efficiency. The researchers suggest microRNAs could replace other genes or improve the efficiency of chemical means of creating iPS cells. In addition, understanding how microRNAs function in reprogramming could lead to new therapeutic strategies for blocking reprogramming in cancer stem cells.



Nature Biotechnology, April 12, 2009
CIRM funding: Robert Blelloch (RS1-00161)

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

Protein protects brain from damage, may prevent neurodegenerative diseases

Researchers at the University of California, San Diego and the Salk Institute for Biological Studies have found a protein that protects the brain from the kind of damage that can lead to Parkinson's disease. This protein, called Nurr1, has a long history in Parkinson's disease research. People who carry a mutation in the gene are prone to developing the disease. The new work explains how the protein prevents Parkinson's disease and could also help researchers find ways of treating of preventing the disease. The protein was especially important in two types of cells that protect and support the brain's neurons -- called microglia and astrocytes. In these cells, Nurr1 works with other proteins to limit inflammation after an immune response. Without it, these support cells produced toxic by-products that damaged the nerves in a way that could lead to Parkinson's disease or other neurodegenerative diseases.

Cell: April 3, 2009
CIRM funding: Beate Winner and Fred H. Gage (RC1-00115), Christian Carson (T3-00007), Leah Boyer (T1-00003)

Related Information: Press release, University of California, San Diego, Salk Institute for Biological Studies, Gage bio

Protein Flips Switch In Embryonic Stem Cell Growth

Researchers at the Burnham Institute for Medical Research and the Scripps Research Institute have found that a protein known to play an important role in maintaining mouse embryonic stem cells has a similarly crucial job in human embryonic stem cells. This protein, called Shp2, acts as a switch, telling the cells to either divide to make more of themselves – a process called self-renewal – or to mature into different cell types – called differentiation. Fine-tuning this balance between self-renewal and differentiation will be critical for developing new therapies based on embryonic stem cells. The cells need to self-renew in order to grow up enough cells to be therapeutically useful. Once researchers have sufficient cells, they need to switch the cells over to a state where they can mature into cell types such as nerves, retinal cells, or pancreatic islets that can be used to study or treat disease.

PLoS ONE: March 17, 2009
CIRM funding: Yuhong Pang (T2-00004)

Related Information: Press Release, Burnham Institute for Medical Research

iPS Cells Mature into Functional Motor Neurons

Researchers at the University of California, Los Angeles have matured induced pluripotent stem (iPS) cells into what appear to be normal motor neurons. This work shows that iPS cells can mature into cells that appear similar to those derived from human embryonic stem cells – a finding that has important implications for people hoping to create new therapies based on iPS cells. These cells are created by reprogramming adult cells back into a pluripotent state that resembles embryonic stem cells. One question has been whether these reprogrammed cells have the same capacity as embryonic stem cells to turn into mature, functioning cell types. This work shows that, at least for motor neurons, iPS and embryonic stem cells have the same capacity to form mature cells. Scientists can study these motor neurons in the lab to learn about – and find cures for – diseases such as amyotrophic lateral sclerosis (Lou Gehrig’s Disease), spinal muscle atrophy or spinal cord injury.

Stem Cells:February 23, 2009 (online publication)
CIRM funding: William Lowry (RS1-00259)

Related Information: Broad Stem Cell Research Center, Lowry lab page

Support Cells Prevent Mature Heart from Repairing Damage

Researchers at the Gladstone Institute of Cardiovascular Disease may have discovered why developing heart muscles cells multiply in numbers while the adult counterparts do not. This finding could lead to therapies that roll back the clocks on heart muscle cells after injury such as a heart attack, allowing those cells to multiply and repair the damage. The researchers specifically looked at the role of cells called fibroblasts, which are packed in the heart amidst the muscle cells. They found that fibroblasts in embryonic mouse hearts release proteins that encourage the muscle cells to divide. In contrast, fibroblasts in adult hearts release proteins that encourage muscle cells to expand in size but actively inhibit the cells from multiplying. That role makes sense in healthy hearts, where new cells aren’t needed, but after injury those fibroblasts prevent the heart from being able to repair itself. The researchers hope this finding could lead to new ways of repairing heart tissue after injury.

Developmental Cell: February 16, 2009
CIRM funding: Deepak Srivastava (RC1-00142), Kathy Ivey (T2-00003)

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

Protein in Pancreas May Lead to New Therapy for Type II Diabetes

Researchers at the Burnham Institute for Medical Research and the University of California, San Diego have found parallels between how the pancreas develops in the embryo and type II diabetes (also known as adult diabetes). When the pancreas develops in an embryo, a protein called Wnt (pronounced “wint) helps control how the cells mature into insulin-producing cells. In most adults, the pancreas contains very little Wnt protein, but in people with type II diabetes Wnt protein is abundant in the pancreas. The authors suggest that Wnt could be a target for new type II diabetes therapies.

Experimental Diabetes Research: January 20, 2009
CIRM funding: Seung-Hee Lee (T2-00004), Carla Demeterco (T2-00003)

Related Information: Press Release, Burnham Institute for Medical Research