How Do Stem Cell Transplants Produce Heart Regeneration?

Stem cell transplants spur greater regeneration in an injured heart that would normally be the case, and so far it appears to be the case that this is a matter of signaling that changes the behavior of native cells rather than the transplanted stem cells integrating with native tissue and generating new cells. Past studies have shown that the stem cells don't last long following transplant. Nonetheless the beneficial effects do last quite a while, and this is presently a mystery - what mechanisms are mediating this result? This is the latest in a line of studies that examine this question, and the novel finding here is that the transplanted cells do leave behind a lingering population of new cells in the heart, but the nature of those cells is unexpected, which is perhaps why past studies have missed them:

In numerous clinical trials, researchers have injected patients with various types of progenitor cells to help heal injured hearts. In some cases, subjects have ended up with better cardiac function, but exactly how has been a subject of disagreement among scientists. According to study on rats, the introduced cells themselves don't do the job by proliferating to create new muscle. "These cells do not become adult cardiac myocytes. So the mechanism is clearly a paracrine action, where the cells release 'something' which makes the heart better. And the million-dollar question now is, 'What is the something?'"

Researchers investigated the fate of so-called c-kit+ cells, progenitors harvested from the heart and named for the presence of a particular kinase. These cells have been the source of a long debate about their role in building cardiac muscle, with some studies finding no evidence of them producing new cardiomyocytes in vivo and others concluding that, if the conditions are right, c-kit cells do indeed make heart muscle. C-kit cells have also been deployed in a clinical trial on heart attack patients. Studies on a variety of cardiac cell therapies have found that the vast majority of the cells don't stick around in the heart for much longer than a few weeks, suggesting that their mode of action is likely not based on the cells themselves producing new muscle tissue directly. To test whether that's the case with c-kit cells, researchers harvested c-kit cells from healthy male rats' hearts and injected them into female rats who had been made to have a heart attack.

Compared to controls, the treated rats had smaller scars, more muscle in their hearts, and improvements in cardiac function. To follow what had happened to the injected c-kit cells, the researchers picked out cells with Y chromosomes, finding that they made up 4 percent to 8 percent of the nuclei in the heart. Many of them had lost c-kit positivity, and it was clear from their morphology that these cells are not heart muscle and don't contribute to cardiac contraction. "Honestly, I do not know what they are. That's what we're trying to figure out." It appeared that the treated animals did have more cell proliferation, which researchers attributes to the cell therapy. "Pretty amazingly, it lasts up to 12 months after transplantation, which is another thing I cannot explain. How can the transplantation, done only once, stimulate a proliferative response for 12 months?"



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