Researchers discover 'sticky' proteins fuse adult stem cells to cardiac muscle, repairing hearts

Cardiologists are increasingly using adult stem cells in clinical trials to repair hearts following heart attacks, but no one has understood how the therapy actually works. Now, in animal experiments, researchers at The University of Texas M. D. Anderson Cancer Center have deconstructed the process, describing how the stem cells fuse with heart muscle cells to create new cells that repopulate the ailing organ.

In a paper posted Feb 15 at Online First of the journal Circulation Research, investigators found that this fusion is only possible if two cell adhesion proteins that stick to each other like Velcro are available to attach a stem cell to a heart muscle cell. They show in cell and mice studies that if either protein is blocked, the two cells don't blend.

The investigators also discovered that these new cells, once fused, divide again in an attempt to produce enough cells to help the heart contract.

"The accepted dogma is that heart cells cannot divide, but we show that fusing stem cells onto muscle cells bestows these cells with a new and wonderful ability to divide again to repair the heart," says the study's lead author Edward T. H. Yeh, M.D., professor and chair of the Department of Cardiology at M. D. Anderson Cancer Center.

"It is marvelous that adult stem cells can help heal a heart, and by understanding the mechanisms involved, we may be able to refine and optimize the process," he says.

But there are not enough natural stem cells available in a body to mount an effective repair response to a heart attack, Yeh says, which is why researchers and clinicians are focused on boosting that response. And in the future, given what the researchers also have discovered about how stem cells can build new cells to line blood vessels, it may be possible to "choose to ether augment rebuilding of heart muscle or restoration of blood vessels, depending on what is therapeutically best for the patient."

This study is the latest undertaken in a focused research program conducted by Yeh and a team of researchers at M. D. Anderson, the Texas Heart Institute at St. Luke's Episcopal Hospital and The University of Texas Health Science Center at Houston to investigate stem cell repair of heart and vascular tissue. In an effort to understand and treat cardiotoxicity related to cancer treatment, M. D. Anderson has one of the largest cardiology programs at any cancer center.

In 2003, the researchers demonstrated that adult stem cells circulating in blood can be used to repair hearts, and that it is not necessary to take the stem cells from bone marrow. In 2004, they found stem cells use different methods to morph into the two kinds of cells needed to restore heart function. In animal studies, they showed that to make new heart muscle cells, the human stem cells fuse onto cardiac cells to produce new muscle (myocyte) cells. But to form new blood vessel cells, the stem cells "differentiate" or mature by themselves to provide new endothelial cells that patch vessel damage.

In this study, they looked into the mechanism by which stem cells fuse to cardiac myocytes. In laboratory experiments, they added adult human stem cells (those that express the CD34+ protein known to be associated with stem cells) to cardiac muscle cells from mice. After 24 hours, some fusion occurred spontaneously - cells were created that had both human and murine protein signatures - but this occurred at a very low rate. They then created conditions that reflect an ongoing heart attack, such as exposing the cells to low oxygen, and saw production of two cytokine molecules, IL-6 and TNF-a, that are part of an inflammatory reaction and which are known to be released when a heart attack occurs. Next, the researchers exposed the cells to all three conditions simultaneously (hypoxia, and extra IL-6 and TNF-a) and found that cell fusion increased 10-fold. "It went from .2 percent of cells becoming fused to 2 percent," Yeh says.

The researchers noted that as a consequence of the experimental "heart attack," expression of two cell surface adhesion molecules was increased. Expression of the protein a4ß1 was induced in the mouse cardiac cells and VCAM-1 was expressed by human stem cells. "The two molecules act like a pair, and stick to each other," Yeh says. "This is the first step to the fusion process."

To double-check that production of a4ß1 and VCAM-1 were critical to cell fusion, the research team added antibodies to each protein into the cell culture, and found fusion couldn't occur.

They then tested the fusion process in mice that don't have an immune system, so they cannot reject the human stem cells. They induced a heart attack in the animals, injected stem cells and saw production of fused cells with signatures donated by each species. However, fusion was markedly reduced in mice given antibodies to a4ß1 and VCAM-1, Yeh says.

The researchers tested whether the adhesion molecules interrupted production of new blood vessel endothelial cells, and found that because fusion is not involved, formation of these cells was not affected. Then they blocked vascular endothelial growth factor (VEGF), a protein known to spur the formation of new blood vessels, and found that if VEGF isn't available, stem cells will not differentiate into new endothelial cells.

Finally, Yeh tested the newly fused heart muscle cells to see what they did after they formed. Heart muscle cells do not divide, so the researchers did not know whether the new fused cells were an endpoint in themselves, designed to replace dying cardiac muscle, or whether they could give rise to other new cells. They discovered that fused cells took on some "stemness" - they divided, and continued to do so as long as new tissue is needed, but not long enough to produce a tumor. "In mice, we have found this process can continue for months," Yeh says.

"We show in these animal experiments that human adult stem cells can form new blood vessels and heart muscle cells, and knowing how these two different processes can be blocked could be very useful in determining the relative contribution of each toward heart repair," he said.

Source: University of Texas M. D. Anderson Cancer Center

Related stories:

Gene directs stem cells to build the heart
Researchers have shown that they can put mouse embryonic stem cells to work building the heart, potentially moving medical science a significant step closer to a new generation of heart disease treatments that use human stem cells.
Sweat, luck and eureka: Recipes for scientific discovery
Every week thousands of academic articles heralding discoveries in medicine and science are vetted and validated before being published in no-nonsense journals with names such as "Acta Crystallographica," "Methods in Enzymology," or "Macromolecules".
Nerve cells derived from stem cells and transplanted into mice may lead to improved brain treatments
Scientists at the Burnham Institute for Medical Research have, for the first time, genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain, according to a study published today in The Journal of Neuroscience. The research, an important step toward developing new treatments for stroke, Alzheimer's, Parkinson's and other neurological conditions showed that mice afflicted by stroke showed tangible therapeutic improvement following transplantation of these cells. None of the mice formed tumors, which had been a major setback in prior attempts at stem cell transplantation.
New source of heart stem cells discovered
Finding offers hope of recapitulating developmental events to regenerate tissue
Researchers at Children's Hospital Boston are continuing to document the heart's earliest origins. Now, they have pinpointed a new, previously unrecognized group of stem cells that give rise to cardiomyocytes, or heart muscle cells. These stem cells, located in the surface of the heart, or epicardium, advance the hope of being able to regenerate injured heart tissue.
European Science Foundation aims to strengthen 'regenerative medicine'
14 Member Organisations of the European Science Foundation have launched a key initiative to keep Europe at the forefront of regenerative medicine; broadly defined as the development of stem cell therapies to restore lost, damaged, or ageing cells and tissues in the human body.
Researchers find key developmental pathway activates lung stem cells
Researchers from the University of Pennsylvania School of Medicine found that the activation of a molecular pathway important in stem cell and developmental biology leads to an increase in lung stem cells. Harnessing this knowledge could help develop therapies for lung-tissue repair after injury or disease. The investigators published their findings online last week in advance of print publication in Nature Genetics.
Researchers create molecule that nudges nerve stem cells to mature
Inspired by a chance discovery during another experiment, researchers at UT Southwestern Medical Center have created a small molecule that stimulates nerve stem cells to begin maturing into nerve cells in culture.
Caution on stem cell therapy
A single organ may contain more than one type of adult stem cell – a discovery that complicates prospects for using the versatile cells to replace damaged tissue as a treatment for disease, according to a new study from the laboratory of geneticist Mario Capecchi, the University of Utah's Nobel Laureate.

News discussion:

Medicine & Health news