News:Study demonstrates that non-cardiac cells can help repair a damaged heart; new excitement for existence of cardiac stem cells. August 26, 2007

August 26, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Boston, MA

New research from Harvard Medical School has demonstrated that heart muscle cells known as cardiomyocytes can be replenished from a pool of non-cardiomyocytes, possibly heart stem cells, following injuries such as a myocardial infarction. These precursor cells do not, however, contribute significantly to the cell repletion that occurs during normal aging.

The authors of this study used a sophisticated mouse transgenic system which allowed them to irreversibly label cardiomyocytes and their daughter cells after addition of a drug, tamoxifen. The tamoxifen acted on a recombinase enzyme that was expressed only in cardiomyocytes. When this enzyme was activated by tamoxifen, it changed the genetic makeup of those cells so that they turned green. After drug wash-out, the existing cardiomyocytes and their descendents remained green because the genetic alteration is permanent and heritable. Cardiomyocytes that developed from another cell type (e.g. a non-differentiated stem cell) would not be green because the cardiomyocyte-restricted recombinase is inactive without tamoxifen.

This elegant genetic model was then used to ask a very simple question about the importance of self-renewal compared to replenishment of cardiomyocytes. The authors found that as mice age, the percentage of green cardiomyocytes did not change, meaning that all the heart muscle cells came from heart muscle cells. In two different models of cardiac injury, however, the results were quite different. Following aortic banding or left coronary artery ligation, the authors noted an increase in the number of non-green cardiomyocytes. Non-cardiomyocyte cells that contribute to cardiomyocyte replenishment could be local or hematopoietic stem cells, or local cells that undergo a transition in phenotype. The interesting possibility is that these non-green cells represent recruitment of stem cells or progenitor cells to replace the damaged myocardium. The authors also note an increase in non-green cells in remote areas, not involved in the infarct. This finding either speaks to a generalized, non-specific signal for progenitor recruitment or a peculiarity of the genetic model.

This exciting new paper raises the possibility that cardiac progenitor cells can replace damaged heart cells after a heart attack. As is true with any transgenic system, prudence requires that we moderate our excitement by acknowledging difficulties with leaky promoters, transgene effects on cell survival, and non-specific genetic effects. Additionally, more work will be needed to isolate these cells and demonstrate the self-renewal capability which defines a true stem cell. If future research identifies these precursor cells or the signals that lead to their differentiation into cardiomyocytes, therapies could be developed to improve this process and help repair damaged hearts.