Adult Hearts Lack Cardiac Stem Cells

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Part of the heart wall of the murine heart after myocardial infarction. Visible are the scar tissue (red) and dead heart muscle cells (pale green). [Hubrecht Institute]

A cell-by-cell search for cardiac stem cells has come up empty, suggesting that previous studies hinting at the existence of cardiac stem cells were mistaken. More significantly, the absence of cardiac stem cells indicates that heart muscle that is lost due to a heart attack cannot be replaced.

The sobering finding was reported by scientists based at the Hubrecht Institute, which is located in the Netherlands. The scientists, led by Hans Clevers, group leader at the Hubrecht Institute and professor of molecular genetics at the University Medical Center Utrecht, published their work this week in the Proceedings of the National Academy of Sciences.

Along with colleagues from École Normale Supérieure de Lyon and the Francis Crick Institute London, the Hubrecht Institute scientists described how they applied the broadest and most direct definition of stem cell function in the mouse heart: the ability of a cell to replace lost tissue by cell division. In the heart, this means that any cell that can produce new heart muscle cells after a heart attack would be termed a cardiac stem cell.

In an attempt to find cardiac stem cells, the scientists generated a “cell-by-cell” map of all dividing cardiac cells before and after a myocardial infarction using advanced molecular and genetic technologies. Details of this work appeared in the PNAS article, which is titled, “Profiling proliferative cells and their progeny in damaged murine hearts.”

“Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types,” the article’s authors indicated in a prepublication version of their paper. “Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of FSTL1 in cardiac fibroblasts results in postdamage cardiac rupture.”

Ultimately, the researchers found no evidence for the existence of a quiescent circulating stem cell population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

Most tissues of animals and humans contain stem cells that come to the rescue upon tissue damage: they rapidly produce large numbers of daughter cells to replace lost tissue cells. Cardiac tissues, however, appear to behave differently. According to the new study, the damaged heart incorporates many types of dividing cells, but none that are capable of generating new heart muscle. In fact, many of the “false leads” of past studies can now be explained: cells that were previously named cardiac stem cells now turn out to produce blood vessels or immune cells, but never heart muscle. Thus, the sobering conclusion is drawn that heart stem cells do not exist.

The authors make a second important observation. Connective tissue cells (also known as fibroblasts) that are intermingled with heart muscle cells respond vigorously to a myocardial infarction by undergoing multiple cell divisions. In doing so, they produce scar tissue that replaces the lost cardiac muscle.

While this scar tissue contains no muscle and thus does not contribute to the pump function of the heart, the fibrotic scar ‘holds together’ the infarcted area. Indeed, when the formation of the scar tissue is blocked, the mice succumb to acute cardiac rupture. Thus, while scar formation is generally seen as a negative outcome of myocardial infarction, the authors stress the importance of the formation of scar tissue for maintaining the integrity of the heart.

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