Cardiac muscle regeneration: lessons from development

Abstract

The adult human heart is an ideal target for regenerative intervention since it does not functionally restore itself after injury yet has a modest regenerative capacity that could be enhanced by innovative therapies. Adult cardiac cells with regenerative potential share gene expression signatures with early fetal progenitors that give rise to multiple cardiac cell types, suggesting that the evolutionarily conserved regulatory networks that drive embryonic heart development might also control aspects of regeneration. Here we discuss commonalities of development and regeneration, and the application of the rich developmental biology heritage to achieve therapeutic regeneration of the human heart.

Figure 1.

Strategies to increase cardiac muscle cell number as a therapeutic target. In principle, the limited ability of the heart to replace cardiomyocytes can be improved by reactivating cell division of pre-existing cardiomyoctes and/or inhibiting cell death or augmenting survival. Alternatively, new myocytes can be produced from multipotent stem or progenitors that reside within niches in the myocardium, circulating stem cells with cardiac potency, or ex vivo cells transplanted into the injured heart. Challenges to regeneration include an endogenous restorative capacity that appears limited by an insufficient number of available stem or progenitor cells, and the need to develop efficient means to produce or deliver exogenous cells. Developmental signals are being investigated for use in enhancing therapeutic regeneration from endogenous and exogenous sources.

Figure 2.

Development and regeneration. Extracellular signaling molecules positively (green) and negatively (red) control mesoderm induction to cardiopoietic differentiation in the embryo. Adult cardiac precursors share genetic markers with their developmental counterparts, and emerging data indicate that developmental signals also control regeneration, suggesting parallels between development and the control of adult cardiomyocyte renewal.