Light shed on regenerative medicine’s biggest secret: cardiomyocyte regenerative capacity

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The myocardial regenerative capacity debate continues with the publication of findings that cellular remodelling may be a lifelong process, with the majority of postnatal cardiomyocyte turnover occurring during the first decade of life.

The study, published in Cell, presents an integrated model of heart cell generation and exchange.
Owing to the substantial health burden caused by heart dysfunction following a cardiac event, research into endogenous cardiac regenerative capacity is exciting; potential cell replacement holds significant clinical promise. However, research to date has presented conflicting evidence over the origin of new cardiomyocytes and the extent of their ability to regenerate, which has raised doubts over any future translational prospects. Estimates of any cell turnover have ranged from zero to complete turnover every few years. However, the researchers assert that previous evaluations based on markers of cell division or cell death have made many assumptions.

The team report that early heart growth occurs through hypertrophy, rather than by an increase in cell number. This growth is also mostly restricted to childhood. Therefore, heart cell generation appears to be modest and just under half of the heart cells may be replaced over a lifetime.

“We examined the heart tissue from 29 deceased individuals of various ages and found that even by one month after birth, the heart contains the same number of cells as it has in adults,” explained co-first author Olaf Bergmann from the Department of Cell and Molecular Biology, Karolinska Institute (Stockholm, Sweden).

The study found that all cardiomyocytes are present perinataly and their number remains constant throughout life. Cardiomyocyte turnover decreases exponentially with age in all main subdivisions of the heart and was found to be <1% annually in adults. On the contrary, numbers of endothelial and mesenchymal cells increase significantly from birth to early adulthood and demonstrate a high turnover. Using the integration of nuclear bomb test-derived 14C uncovered a turnover rate of >15% each year for endothelial cells but a lower rate of <4% per year for mesenchymal cells, which also demonstrate an age-related decline. This means that endothelial cells completely renew themselves every six years. “Our study shows that endothelial cells, mesenchymal cells and heart muscle cells are renewed in the human heart throughout life, albeit at a different rate for different cells,” reported study leader Jonas Frisén, Professor in Stem Cell Research at Karolinska Institute. “Our findings suggest that it can be rational and realistic to develop new therapeutic strategies for strengthening the body’s own regenerative capacity to treat heart diseases.” Sources: Bergmann O, Zdunek S, Felker A et al. Dynamics of Cell Generation and Turnover in the Human Heart. Cell, doi:10.1016/j.cell.2015.05.026; Most heart muscle cells formed during childhood;