Mechanisms of myocardial regeneration

Abstract

Traditionally, the adult heart has been viewed as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at birth and these cells persist throughout the life span of the organ and organism. However, the discovery that cardiac stem cells live in the heart and differentiate into the various cardiac cell lineages has dramatically changed our understanding of myocardial biology. Deciphering the biological processes that lead to myocyte renewal is a challenging task. Cardiac regeneration may be accomplished by (1) commitment of multipotent stem cells that generate all specialized lineages within the parenchyma, (2) activation of unipotent progenitors with restricted differentiation potential, (3) replication of pre-existing differentiated cells, (4) transdifferentiation of exogenous progenitors that undergo plastic conversion into cells different from the organ of origin, and (5) dedifferentiation of cardiomyocytes that re-enter the cell cycle and divide. These multiple mechanisms of cell growth may act in concert to regenerate complex structures and restore the function of the target organ.

Figure 1

Myocyte cytokinesis. Panels A and B: Chromosomes (blue: PI, propidium iodide) are labeled by the cell cycle protein Ki67 (yellow) in cardiomyocytes (cardiac myosin heavy chain, MHC, red). Arrows point to cytokinesis. Panel C: Mitotic figure in an isolated binucleated mouse myocyte (α-sarcomeric actin, α-SA, red).

Figure 2

Cardiac stem cells and their progeny in vitro and in vivo. Panel A: Phase contrast microscopy. Single cell-derived clones from c-kit-positive human CSCs. Panel B: c-kit-positive human CSCs exposed in vitro to differentiation medium form myocytes (α-SA, red), endothelial cells (von Willebrand factor, vWf, yellow) and smooth muscle cells (α-smooth muscle actin, α-SMA, green). Panel C: Human CSCs regenerate infarcted myocardium in an immunodeficient mouse heart 21 days after infarction and cell delivery. Human myocardium (arrowheads) is present within the infarct (MI). BZ, border zone. Areas in rectangles are shown at higher magnification below. Human myocytes are α-SA (red) and Alu probe (green) positive. Alu documents human DNA sequences in the newly-formed myocardium. Asterisks, spared myocytes.