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 functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is key 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=67), CDCs (n=36) or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to CDC- or saline-treated MI controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle and endothelial cells could be identified in CBSC- but not in CDC-treated animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP- myocytes. Conclusions CBSCs improve survival, cardiac function, and attenuate remodeling through two mechanisms:1) secretion of pro-angiogenic factors that stimulate endogenous neovascularization, and 2) differentiation into functional adult myocytes and vascular cells.

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

“…37 After lineage commitment, all 3 stem cell types expressed paracrine factors known to be responsible for improvements in cardiac function after stem cell transplantation (Figure 3). In our previous published findings, we have shown that, after 24 hours and 2 weeks of CBSCs transplantation, levels of paracrine factors including bFGF and VEGF are upregulated 1 and could account for enhanced neovascularization previously observed in CBSCs-injected animals after ischemic insult. Similarly, these paracrine factors are also known to have protective effects on heart.…”

“…Heart tissue was digested in collagenase and c-kit sorted as described earlier. 1 CDCs were cultured in CBSCs media.…”

“…Research from several laboratories, including ours, suggests that stem cells hold immense potential for cardiac repair and regeneration. [1][2][3][4] Clinical use of adult stem cells is a reality today and many stem cell types, including bone marrow-derived mesenchymal stem cells (MSCs), 5 bone marrow cells, 7,8 cardiac-derived cardiac progenitor, 6 and cardio-sphere derived cells 9 have been tested. The beneficial effects of tested cell therapies on cardiac structure and function have been modest and most studies to date have not been adequately powered to document efficacy.…”

Circulation Research “In This Issue” Anthology

“…Bone-Derived Stem Cells Repair the Heart (p 539) 50 Believe it or not, bone stem cells are better than cardiac stem cells for repairing a damaged heart, say Duran et al…”

Steven Houser

“…Houser's lab recently demonstrated that cortical bone-derived stem cells may be superior to cardiac stem cells in regenerating heart tissue after MI. 8 Houser, 63, director of the Cardiovascular Research Center and chair of physiology at Temple, tells Circulation Research he's never afraid to jump into a scientific argument 9 and help inform the debate. His strategy is always fair and careful experimentation, with an emphasis on reproducible findings.…”