C-kit+VEGFR-2+ Mesenchymal Stem Cells Differentiate into Cardiovascular Cells and Repair Infarcted Myocardium after Transplantation

Abstract:

Background: Resent preclinical studies and clinical trails prove that transplantation of mesenchymal stem cells (MSCs) is a promised therapy for ischemic diseases. However, the properties of c-kit⁺ cells in MSCs remain unclear. We investigatedthe differential potential of c-kit⁺VEGFR-2⁺ MSCs and evaluated their effects on repairing the infarcted myocardium after transplantation.

Methods: c-kit⁺VEGFR-2⁺ MSCs were isolated from rat bone marrow. Gene expression profile of the cells was examined with RNA-sequencing. Differential potential of the cells was determined after induction with VEGF, TGF-β and BMP-2 for 2 weeks. Improvement of cardiac function and repair of the infarcted myocardium were assessed at 4 weeks after transplantation of the cells preconditioned with hypoxia and serum deprivation.

Results: Gene expression profile revealed that the upregulated genes are enrichment of genes related to immune process and cell differentiation. The cells represented a potential of differentiation towards endothelial cell, smooth muscle cells and cardiamyocytes. In hypoxic condition, secretion of VEGF, SCF and SDF-1α from the cells was increased. VEGF and SCF promoted proliferation and migration of the cells. VEGF could induce the cells to incorporate to the microvessels. After transplantation of the preconditioned cells into the infarcted myocardium, cardiac function was improved, scar size of the infarcted myocardium was decreased, and angiogensis and myocardium repair were enhanced significantly. With preconditioning and delivery by fibrin gel, survival of the cells in the ischemic tissue was augmented.

Conclusion: These results suggest that c-kit⁺VEGFR-2⁺ MSCs have a potential of differentiation towards cardiovascular cells. SCF/c-kit and VEGF/VEGFR-2 singnalling pathways regulate proliferation, migration and differentiation of the cells. Transplantation of c-kit⁺VEGFR-2⁺ MSCs may enhance repair of the infarcted myocardium effectively.