Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms

Abstract

Rationale: Autologous bone marrow- or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials but has only offered limited functional improvements. Finding the optimal stem cell type best suited for cardiac regeneration remains a key goal toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone stem cells (CBSCs) and cardiac-derived stem cells (CDCs) were isolated from EGFP+ transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction (MI) with injection of CBSCs (n=57), CDCs (n=31) or saline (n=57). Cardiac function was monitored using echocardiography with strain analysis. EGFP+ CBSCs in vivo were shown to express only 2/8 factors tested (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC and CDC therapy improved survival, cardiac function, attenuated adverse remodeling, and decreased infarct size relative to saline-treated MI controls. CBSC treated animals showed the most pronounced improvements in all parameters. By 6 weeks post-MI, EGFP+ cardiomyocytes, vascular smooth muscle cells and endothelial cells could be identified on histology in CBSC-treated animals but not in CDC-treated animals. EGFP+ myocytes isolated from CBSC-treated animals were smaller, more frequently mononucleated, and demonstrated fractional shortening and calcium currents indistinguishable from EGFP- myocytes from the same hearts. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling more so than CDCs and this occurs through two mechanisms: 1) secretion of the proangiogenic factors bFGF and VEGF (which stimulates endogenous neovascularization), and 2) differentiation into functional adult myocytes and vascular cells.