Myocardial Remodeling in Embryonic Heart: An Inductive Interaction Mediated by Periostin

Abstract

Where mesenchyme in the developing heart contacts adjacent myocardial tissue the myocardium progressively “disappears”. It is replaced by fibrous tissue (e.g. the fibrous annulus or tendinous cords). Periostin, a fasciclin-related protein, is secreted by the mesenchyme which accumulates at boundary interfaces. Similarly, periostin increases in adult hearts undergoing either ischemic or non-ischemic myocardial remodeling that leads to scarring. In periostin null adult hearts, myocardial tissue that normally regresses persists and is frequently accompanied by premature heartbeats of non-sinus origin. Based on cell sorting data, there were more myocardial cells in periostin adult null hearts but 30% of the cells remained undifferentiated. We hypothesized that periostin promoted fibroblast differentiation but inhibited myocardial differentiation or stability of the myocardial phenotype. To test this hypothesis, we used adenoviral vectors expressing full-length periostin protein in culture assays or in vivo. When added to culture media of E.D. 13 explants containing mesenchyme and myocardium, the latter was reduced (~80%) but fibroblastic tissue proliferated. Direct injection of the virus (but not controls) into the pericardial space or ventricular walls resulted in myocardial thinning and loss of compact myocardium. Co-culturing monolayers of mesenchyme with embryonic myocardial cells separated by a barrier resulted in progressive loss of myofibril organization in myocytes. As there was no evidence of augmented apoptosis at boundary interfaces either in vivo or in cultured monolayers, we propose that periostin induces loss of myocardial tissue, possibly through a transdifferentiation mechanism. Supported by HL 33576, HL53228