Stem cells for a broken heart? Maybe one day

The LA Times has a timely story in the week leading up to Valentine’s day summarizing the role of stem cells in mending a broken heart. There’s been a lot of talk — and a lot of money invested -- over the past few years pushing bone marrow stem cells as a tool for repairing damage after heart attack.

I remember back in 2004 I wrote about Stanford’s Robert Robbins who had transplanted bone marrow stem cells into the hearts of mice with induced heart attacks. He found a temporary improvement in those mice, but that improvement didn’t last. In the end, their hearts were just as broken as their untreated lab-mates and the mice died at the same rate.

Years later, his result seems to have held up in people. From the LA Times:

From 2002 to 2006 alone, there were at least 18 randomized controlled studies involving nearly 1,000 patients.

"Everyone started putting bone marrow in the heart," says Christine Mummery, a researcher at Leiden University Medical Center in the Netherlands, who has studied how to turn stem cells into heart muscle cells called cardiomyocytes.

But the results, she says, were a mixed bag. The treatment appeared to be safe, but patients had only transient improvement.

"People went from being very sick to a little less sick," Mummery says.

These doubts about bone marrow stem cells for repairing heart damage haven’t discouraged CIRM grantees working with other stem cell types. CIRM grantee Eduardo Marban, who is director of the Cedars-Sinai Heart Institute in Los Angeles, has CIRM funding to use the heart’s own stem cells as a repair mechanism after heart attack. He is quoted in the LA Times story as saying:

The hope is that the cardiac stem cells will take root and reverse the scar. Results should be out later this year. "Let's just say we're extremely encouraged," Marbán says. "It looks like it's working, and cleanly."

Over at the Gladstone Institute of Cardiovascular Disease in San Francisco, CIRM grantee Deepak Srivastava has devised a way of directly converting heart connective tissue into heart muscle, at least in rodents. That work is still years from clinical trials — or even being proven to work in human cells — but has caused a stir in stem cell circles.

Still other CIRM grantees throughout the state are prodding human embryonic stem cells to mature into heart tissue that could be transplanted into the heart as a sort of cellular patch for the damaged region.

None of these approaches will arrive in time to repair a broken heart on this Valentine’s day, but one day down the road stem cells of some type — whether it’s heart stem cells, directly reprogrammed cells or embryonic stem cell derived — might be what patches up damaged hearts of the future.

Here’s a complete list of CIRM funding for heart disease.

A.A.

Stem cells model heart disease, test drugs

Nature has a story that features a promising use for stem cells, and also provided a creative outlet for whoever is writing headlines over there: “Cells snag top modelling job”.

Nature isn’t covering America’s top model. They’re talking about modeling disease, in this case a heart condition called long QT syndrome. Both embryonic or iPS cells can be matured into any adult cell type. If those cells carry mutations that cause disease then they’ll mature into adult cell types that, in some cases, display that disease.

For something like long QT syndrome, in which the heart tissue has an altered beat, stem cells carrying a mutation that causes the condition provide the only way of testing drugs in a lab. The story mentions Mike Venuti, president of CIRM-funded biotech company iPerian:

His firm has made iPS cells from people with Alzheimer's disease, Parkinson's disease and type 2 diabetes and converted them into various cell types for drug screening. He expects that drugs identified using this method will reach clinical trial for conditions such as spinal muscular atrophy in the next few years.

CIRM funds work by Bruce Conklin at the Gladsone Institute of Cardiovascular Disease, who is taking cells from people with heart conditions, creating iPS cells, and using those cells to study the condition and test drugs. This video features Conklin discussing his cells’ top modeling work.



- A.A.

Top four list: why embryonic stem cells are critical

Yesterday CIRM grantee Bruce Conklin gave his top four reasons why embryonic stem cells are so valuable and why federal funding for the work needs to be able to continue. Conklin, who is Senior Investigator Gladstone Institute of Cardiovascular Disease and professor at UCSF, studies heart rhythm defects by creating iPS cells from people genetically predisposed to have those defects, then maturing those into heart cells in a dish. This gives him a way of studying the rhythm defect in the lab, and allows him to test drugs that might correct the arrhythmia. (You can see his New Cell Lines Award research summary here.)

Conklin says he’d never be able to carry out his iPS work without advances made with embryonic stem cells. Here’s his list:

1) Scientists have genetically engineered embryonic stem cells that are widely used for studying specific processes in the lab. “Obviously, we can remake those cells lines using iPS cells but it’s a huge waste of time,” he said. Instead of making progress toward developing new therapies or finding new drugs, labs would have to spend years redoing work they’ve already done.

2) Embryonic stem cells are farther along clinically than iPS cells or the new directly reprogrammed cells. “The first clinical trials of pluripotent cells will be embryonic stem cells. Ten years from now we’ll probably see a mix of embryonic and iPS cells,” he predicted. Adult cells are good for many things, he said, but aren’t as flexible as pluripotent embryonic or iPS cells.

3) Embryonic stem cells reproduce the steps taken by nature. “The idea is that nature knows something we don’t, because we don’t know very much,” Conklin said. Studying embryonic stem cells as they go down the path toward a specific cell type, like a skin cell or a neuron or a pancreatic islet cell, can give us clues about what might be going wrong in diseases afflicting those cell types.

4) Some diseases seem to begin at the earliest stages of development. “If we are going to understand human development we have to know how the process happens naturally,” he said. Only by studying embryonic stem cells can we understand genetic diseases that strike at the earliest stage, or what’s called epigenetic changes that can alter the way genes function.

Conklin seemed optimistic about the future of iPS and direct reprogramming, but pointed out that even Jamie Thomson, who was part of one of the two teams that first created iPS cells, has predicted that iPS cell research would be five years ahead of where it is now if embryonic stem cell research weren’t slowed under the Bush funding regulations.

The CIRM Governing Board recently passed a resolution that “strongly encourages federal policy that supports all forms of stem cell research for the millions of Americans who suffer from disease and injury and strongly supports criminalizing human reproductive cloning.” You can read Resolution 2010-01 here, which supports both the DeGette and Spector legislation “or any successor legislation that embodies the policies advanced in President Obama’s Executive Order 13505 and the National Institutes of Health July 7, 2009 guidelines on hESC research.”

A.A.

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.

Fibroblasts reprogrammed to heart cells

Cardiac muscle (red) with reprogrammed
fibroblasts (green). Srivastava lab.

The dogma was once that mature cell types like skin or nerves needed to be reprogrammed to an embryonic-like state before they could mature into a different cell type. Essentially, if a cell was a doctor it would need to go back to kindergarden before it could grow up to become a lawyer.

That was until last year when Doug Melton and his team at the Harvard Stem Cell Institute did the equivalent of sending the cellular doctors directly to law school. They succeeded in converting one type of mouse pancreatic cell directly into the pancreatic beta cells that produce insulin. Earlier this year, Stanford scientist Marius Wernig carried out a similar feat, turning skin cells into nerve cells.

Now another CIRM grantee — this time Deepak Srivastava at the Gladstone Institute of Cardiovascular Disease and UCSF — has bypassed the embryonic state. He reprogrammed mouse fibroblasts directly into primitive heart cells. In a press release, Srivastava said:

“The ability to reprogram fibroblasts into cardiomyocytes has many therapeutic implications. Half of the cells in the heart are fibroblasts, so the ability to call upon this reservoir of cells already in the organ to become beating heart cells has tremendous promise for cardiac regeneration."

This work builds on work by another Gladstone scientist. Shinya Yamanaka was the first to reprogram adult cells to an embryonic state called induced pluripotent stem (iPS) cells. What Srivastava, Wernig and Melton have shown is that this initial reprogramming step may not always be needed to create therapeutic cell types. Avoiding the embryonic state may avoid the tumor-causing potential of embryonic cells and may have other advantages, according to the Gladstone release. However, Srivastava points out that this cellular career switch has yet to succeed in human cells.

Cell, August 5, 2010
CIRM Funding: Deepak Srivastava (RC1-00142-1), Benoit Bruneau (RN2-00903-1)

A.A.

Shinya Yamanaka receives Kyoto prize for reprogramming skin cells

Last week, while stem cell researchers from around the world congregated in San Francisco for their annual meeting, stem cell pioneer Shinya Yamanaka won the Kyoto Prize for Advanced Technology. This award in generally considered to be a precursor to a Nobel Prize.

A press release from UCSF said:

Yamanaka received the prize for his discovery of a method of reprogramming adult skin cells to become embryonic-like stem cells. The discovery has opened up the field of stem cell research and dramatically changed the field of cell biology. He also is affiliated with and has a research lab at Kyoto University.

Yamanaka has a lab at the Gladstone Institute of Cardiovascular Disease in San Francisco, which is affiliated with UCSF. He does not have CIRM funding, but the Institute does have shared lab space funded by CIRM for carrying out stem cell research.

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

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

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

Genetic Factor Enables Immature Cells to Form Normal Heart Tissue

Researchers at the Gladstone Institute for Cardiovascular Disease found a genetic factor that helps in the earliest stages of heart development as the primitive tube loops around on itself and forms the separate chambers. This factor -- a short relative of DNA called microRNA -- has an identical counterpart in humans, leading the researchers to believe that their work in fish is likely to relate directly to human heart development. When the researchers interfered with this microRNA while the heart was developing, the immature heart muscle cells failed to mature and the heart chambers didn’t form normally. These heart muscle precursors are a stage in between the embryonic stem cell and the mature heart muscle cell. The heart is among the first organs to develop and also the most critical. When the heart doesn’t develop properly the embryo dies. What’s more, common birth defects involve abnormalities in how these chambers form. Understanding all the steps between an embryonic stem cell and the mature heart cell could help researchers prevent or treat birth defects of the heart.

Proceedings of the National Academy of Sciences: November 12, 2008
CIRM funding: Kathy Ivey (T2-00003), Deepak Srivastava (RC1-00142)

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

Genetic Factor Influences Heart Muscle Formation from Embryonic Stem Cells

Researchers at the Gladstone Institute for Cardiovascular Disease discovered how two specific tiny genetic factors called microRNAs influence the differentiation of embryonic stem cells into heart muscle. They found that the factors not only drive the versatile cells to become heart, but also actively prevent them from becoming other tissue such as bone adding to their potential to make therapy more specific and targeted for patients.

Cell Stem Cell: March 6, 2008
CIRM funding: Kathey Ivey (T2-00003), E. Hsiao (T2-00003), Deepak Srivastava (RC1-00142)

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