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.

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

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

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

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

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

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

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

Knoepfler writes:

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

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

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

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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)

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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