Stimulatory Effects of Mesenchymal Stem Cells on cKit ⁺ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways

Abstract

Rationale Culture expanded cells originating from cardiac tissue that express the cell surface receptor cKit are undergoing clinical testing as a cell source for heart failure and congenital heart disease. While accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit+ cells (CSCs), the underlying mechanism for this synergistic effect remain incompletely understood. Objective To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and SCF/cKit pathways. Methods and Results Using genetic lineage-tracing approaches we show that in the postnatal murine heart, cKit+ cells proliferate, migrate, and form cardiomyocytes, but not endothelial cells. CSCs exhibit marked chemotactic and proliferative responses when co-cultured with MSCs but not cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (p<0.0001). Furthermore, MSCs enhanced CSC proliferation via the SCF/cKit and SDF1/CXCR4 pathways (p<0.0001). Conclusions Together these findings show that MSCs exhibit profound, yet differential, effects upon CSC migration, proliferation and differentiation, and suggest a mechanism underlying the improved cardiac regeneration associated with combination therapy using CSCs and MSCs. These findings have important therapeutic implications for cell-based therapy strategies that employ mixtures of CSCs and MSCs.

C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

“…Because adult mammalian hearts have very limited regenerative capacity, stem cell therapy is a potential strategy regenerating myocardium 2 . Multiple preclinical studies utilizing mesenchymal stem cells (MSCs) have been conducted, demonstrating favorable impact on left ventricle remodeling 3–5 . However, the favorable results observed in animal study have not been fully translated to patients with myocardial infarction (MI) and HF, due largely to the poor survival of engrafted MSCs in the ischemic environment 6 .…”

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

“…MSCs have been shown to exert their reparative effects by 4 main mechanisms: decrease in fibrosis, increase in neovascularization, and immunomodulation, as well as direct enhancement of endogenous stem cell activity 5, 35, 36. Few clinical trials have been conducted on patients with DCM,1, 37 further stressing the importance of understanding the differences in responses to cell therapy compared to ICM.…”

Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit + Cells

“…One potential factor influencing the decision of c-kit + cells to become endothelial cells or cardiomyocytes might be wall-stress mediated factors, although additional factors, such as paracrine mediators may also be involved. 27, 39 Moreover, how these initiating factors in turn stimulate c-kit + CPCs to differentiate will be important to identify specific differentiation pathways that are relevant for adult CPCs. Identification of these pathways may further improve the efficacy of cell therapy, which is likely mediated by paracrine effectors that stimulate endogenous cells, such as c-kit + cells.…”