MicroRNA-21 is a key determinant in IL-11/Stat3 anti-apoptotic signalling pathway in preconditioning of skeletal myoblasts

Abstract

AimsWe have previously shown that preconditioning of stem and progenitor cells promotes their survival post-engraftment in the infarcted heart. The present study was designed to (i) delineate the role of microRNA-21 (miR-21) in interleukin-11 (IL-11) signalling during preconditioning of skeletal myoblasts (MY) and (ii) study the long-term fate of preconditioned MY (PCMY) post-transplantation in the infarcted heart. Methods and results: We report that pharmacological preconditioning of MY with diazoxide showed robust expression of IL-11 and activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and signal transducers and activators of transcription-3 (Stat3) with concomitantly increased miR-21. These molecular events improved cytoprotection of PCMY under oxidant stress in vitro which was compromised by pre-treatment of PCMY with IL-11-specific siRNA, Erk1/2 blocker, or anti-miR-21. In vivo studies for sry-gene detection in a female rat heart model of acute myocardial infarction showed two-fold higher survival of male donor PCMY 4 and 7 days post-engraftment. Long-term fate of the engrafted cells was determined at 4 months after transplantation. Immunohistological studies revealed that in comparison with non-PCMY, PCMY improved angiogenic response in the heart which was evident from a higher number of blood vessels per surface area (0.155 mm2) and myogenic differentiation of PCMY in the heart. Indices of myocardial contractility including ejection fraction and fractional shortening showed significant improvement in PCMY-treated animals. Conclusion: miR-21 is a key regulator of Erk1/2-Stat3 signalling downstream of IL-11 during preconditioning of MY. The therapeutic benefits of PCMY were stable and persisted until 4 months of observation. © The Author 2010.