Stimulatory Effects of MSCs on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways
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.
- Received June 10, 2016.
- Revision received July 18, 2016.
- Accepted July 29, 2016.