Figure 4.

Therapeutic strategies for cardiac regeneration

(Left) Cell-based therapies involve transplantation into the damaged heart of in vitro-derived cardiomyocytes (CMs) or somatic stem cells. CM differentiation can be induced from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) obtained by reprogramming differentiated somatic cells, such as fibroblasts. Alternatively, by forced expression of cardiac-specific factors, the pluripotent state can be bypassed and fibroblasts directly converted into CMs or cardiac progenitor cells (CPCs). Different types of cardiac and non-cardiac somatic stem cells can also be transplanted. Cell-based therapies can produce beneficial effects on heart function directly, by engrafting into the host tissue and differentiating/proliferating in vivo, or indirectly via paracrine effects that act on host cells. (Right) Cell-free therapies involve administration of chemical compounds or genes (via viral vectors, non-viral DNA vectors, or modified mRNAs) that act on host cells to stimulate cardiac regeneration. Mechanisms of action include the stimulation of proliferation of preexisting CMs, direct conversion of cardiac fibroblasts (CFs) into CMs, trans-differentiation of CMs or other cardiac cells from one cellular subtype to another, and activation and differentiation of endogenous CPCs. Cardiac delivery routes for both cell-based and cell-free therapeutic agents are also indicated.