Manipulation of a Master Molecular Switch Called 190RhoGAP May Improve Stem Cell Treatment Of Heart Attacks


New research findings have provided vitals clues as to why heart-based stem cells differentiate into muscle or blood vessels. Such a discovery might hold the key to better treatments for heart attacks in the future.

Human heart tissue lacks the capacity to heal after a heart attack and instead of reforming heart muscle; it tends to form a non-contracting heart scar. Stem cells in the heart can augment the healing process and direct the heart to make heart muscle and blood vessels rather than scars, but why this does not normally occur is unclear.

Particular physicians and their colleagues have shown that introducing heart stem cells into the heart can reduce the formation of heart scar tissue and increase the regeneration of heart muscle. However, uncovering the molecular switch that directs the fate of these cells could result in even more effective treatments for heart patients.

A recent report has shown that scientists who have manipulated a protein called “p190RhoGAP” managed to direct the differentiation of cardiac stem cells to become either blood vessels or heart muscle. Members of this research group even said that altering levels of this protein can affect the activities of these stem cells.

Andre Levchenko, a biomedical engineering professor who supervised the research effort said: “In biology, finding a central regulator like this is like finding a pot of gold.” The lead author of this paper, Kshitiz, said, “Our findings greatly enhance our understanding of stem cell biology and suggest innovative new ways to control the behavior of cardiac stem cells before and after they are transplanted into a patient. This discovery could significantly change the way stem cell therapy is administered in heart patients.”

Earlier in 2012, a medical team at Cedars-Sinai Medical Center in Los Angeles, CA reported reductions of scar tissue in heart attack patients after harvesting some of the patient’s own cardiac stem cells, growing more of these cells in the lab and then transfusing them back into the patient. Using the stem cells from the patient’s own heart prevented the rejection problems that often occur when tissue is transplanted from another person.

The goal of Levchenko’s research is to determine what directs the stem cells, at the molecular level, to change into helpful heart tissue. Answering this question could improve the results from experiments like the one done at Cedars-Sinai and boost regeneration in the heart after a heart attack to an even greater degree.
Levchenko’s team (from Johns Hopkins) tried to change the surface upon which they grew the harvested cardiac stem cells. Surprisingly, growing the cells on a surface that had a similar rigidity to that of heart tissue caused the stem cells to grow faster and to form blood vessels. The increase in growth was substantially greater than that observed with any other protocol with regard to these stem cells. The increased population growth on such a medium also gave prominent hints as to why the formation of a cardiac scar (a structure with very different rigidity), can inhibit stem cells that reside there from regenerating the heart.

By digging further into this phenomenon, the Johns Hopkins group found that the increased cell growth under these conditions was due to decreases in the levels of a protein called p190RhoGAP. This same molecule, when absent, could also direct stem cells to form blood vessels.
Levchenko explained: “It was the kind of master regulator of this process. And an even bigger surprise was that if we directly forced this molecule to disappear, we no longer needed the special heart-matched surfaces. When the master regulator was missing, the stem cells started to form blood vessels, even on glass.”

When Levchenko’s group artificially increased levels of 190RhoGAP, the stem cells formed heart muscle. According to Levchenko, “The stem cells started to turn into cardiac muscle tissue, instead of blood vessels. This told us that this amazing molecule was the master regulator not only of the blood vessel development, but that it also determined whether cardiac muscles and blood vessels would develop from the same cells, even though these types of tissue are quite different.”

Can such findings make a difference in the treatment of living beings? To get a handle on the clinical consequences of this finding, Levchenko’s group limited the production of p190RhoGAP in cardiac stem cells not within a culture dish, but inside the heart of a living animals. The cells with less 190RhoGAP integrated more smoothly into an animal’s blood vessel networks in the aftermath of a heart attack. Also, more of these transplanted heart cells survived, compared to what had occurred in earlier cell-growing procedures.

Kshitiz said that the special heart-like surface on which the cardiac stem cells were grown triggers regulation of the master molecule, and this then guides the next steps in differentiation.

“This single protein can control the cells’ shape, how fast they divide, how they become blood vessel cells and how they start to form a blood vessel network,” he said. “How it performed all of these myriad tasks that require hundreds of other proteins to act in a complex interplay was an interesting mystery to address, and one that rarely occurs in biology. It was like a molecular symphony being played in time, with each beat placed right at the moment before another melody has to start.”
See Matrix Rigidity Controls Endothelial Differentiation and Morphogenesis of Cardiac Precursors;” Kshitiz et al; Science Signaling, 2012; 5 (227): ra41 DOI: 10.1126/scisignal.2003002.