Bone Marrow-Derived Cell Therapy Stimulates Endogenous Cardiomyocyte Progenitors and Promotes Cardiac Repair

SummaryCell therapy can improve cardiac function in animals and humans after injury, but the mechanism is unclear. We performed cell therapy experiments in genetically engineered mice that permanently express green fluorescent protein (GFP) only in cardiomyocytes after a pulse of 4-OH-tamoxifen. Myocardial infarction diluted the GFP+ cardiomyocyte pool, indicating refreshment by non-GFP+ progenitors. Cell therapy with bone marrow-derived c-kit+ cells, but not mesenchymal stem cells, further diluted the GFP+ pool, consistent with c-kit+ cell-mediated augmentation of cardiomyocyte progenitor activity. This effect could not be explained by transdifferentiation to cardiomyocytes by exogenously delivered c-kit+ cells or by cell fusion. Therapy with c-kit+ cells but not mesenchymal stem cells improved cardiac function. These findings suggest that stimulation of endogenous cardiogenic progenitor activity is a critical mechanism of cardiac cell therapy.

Graphical AbstractFigure optionsDownload high-quality image (203 K)Download as PowerPoint slideHighlights
► c-kit+ cell therapy stimulates endogenous cardiomyocyte progenitors
► Nkx2.5- and Gata4-expressing progenitors increase in the infarct border zone
► c-kit+ cell therapy leads to improved cardiac function
► No evidence for cardiomyocyte transdifferentiation by bone marrow progenitors