Cardiac Regeneration and Stem Cells

Abstract

After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world.

FIGURE 1.

Potential sources of new cardiomyocytes in the adult heart. Schematic diagram summarizing the potential sources of new cardiac myocytes that have been proposed to contribute to myocyte turnover in the adult heart.

FIGURE 2.

Multiple cell fates are associated with DNA synthesis and reexpression of cell cycle proteins. Multinucleation (DNA replication with karyokinesis but no cytokinesis), polyploidization (DNA replication without karyokinesis or cytokinesis), fusion of nonmyocytes with cardiac myocytes, or DNA repair can all be associated with DNA synthesis and/or reexpression of cell cycle proteins but does not necessarily represent true cardiac myocyte division.

FIGURE 3.

Regenerated cardiomyocytes are derived from preexisting cardiomyocytes not progenitor cells. Schematic diagram of genetic lineage tracing strategy used in zebrafish to identify the source of new cardiac myocytes in the regenerated heart. Cardiomyocytes in transgenic zebrafish were genetically labeled by inducing Cre activity with tamoxifen. These embryos were then grown to adulthood when the heart was amputated and allowed to regenerate. Preexisting cardiomyocytes (green: GFP+) in the injure borderzone dedifferentiate and proliferate to regenerate the resected apex over a period of 30 days.

FIGURE 4.

Strategies to regenerate adult heart after injury. Schematic diagram depicting strategies, outlined in the text, for regenerating new heart muscle after cardiac injury.