Dose-dependent systolic contribution of differentiated stem cells in post-infarct ventricular function

Background

Differentiation of bone marrow stem cells toward cardiomyocytes has been widely reported in vitro. However, optimum cell types and mechanisms leading to functional improvement in cardiac cell therapy remain unresolved. There is limited evidence showing a dose-dependent effect of transplanted cells in contributing to functional recovery. This study showed that cell transplantation of differentiated cardiomyocyte-like cells (CLCs) and undifferentiated mesenchymal stem cells (MSCs) dose-dependently improved left ventricular function in a rat myocardial infarction model.

Methods

At 1 week after infarction in Wistar rats, 1 × 10⁶ MSCs (n = 9) or CLCs (n = 9) and 5 × 10⁶ MSCs (n = 18) or CLCs (n = 15) were injected into peri-infarcted myocardium to study their effect after 6 weeks.

Results

High-dose CLCs exhibited a dose-response that was significantly more effective than MSCs in recovering cardiac contractility. Superiority of CLCs over MSCs was demonstrated in load-independent measurement of the end-systolic pressure-volume relationship and pre-load recruitable stroke work, but not in the end-diastolic pressure-volume relationship. These findings showed a unique systolic role of CLCs in contractility recovery. Functional improvement mediated by MSCs was mainly derived from preservation of endogenous myocyte function and restriction of chamber dilatation by enhancing intramyocardial angiogenesis during post-infarct ventricular remodeling. Engrafted CLCs showed better survival, were strategically integrated into myofiber-associated collagen V matrix, and exhibited mature sarcomeric cross-striations. Vascular differentiation, but not cardiac, was observed with MSCs.

Conclusion

These cell type-specific effects suggest that committing stem cells to a cardiac phenotype ex vivo promoted mechanical and functional integration of CLCs into the myofibrillar syncytium of infarcted myocardium.

Keywords: stem cell, cell therapy, ventricular remodeling, myocardial infarction, cardiac hemodynamic, myocardial contractility