An autocrine synergistic desmin-SPARC network promotes cardiomyogenesis in cardiac stem cells.

Abstract

The mammalian heart contains cardiac stem cells throughout life, but it has not been possible to harness or stimulate these cells to repair damaged myocardium in vivo. Assuming physiological relevance of these cells, which have evolved and have been maintained throughout mammalian evolution, we hypothesize that cardiac stem cells may contribute to cardiomyogenesis in an unorthodox manner. Since the intermediate filament protein desmin and the matricellular Secreted Protein Acidic and Rich in Cysteine (SPARC) promote cardiomyogenic differentiation during embryogenesis in a cell-autonomous and paracrine manner, respectively, we focus on their genes and employ mouse embryonic and cardiac stem cell lines as in vitro models to ask whether desmin and SPARC cooperatively influence cardiomyogenesis in cardiac stem and progenitor cells. We show that desmin also promotes cardiomyogenesis in a non-cell autonomous manner by increasing the expression and secretion of SPARC in differentiating embryonic stem cells. SPARC is also secreted by cardiac stem cells where it promotes cardiomyogenesis in an autocrine and concentration-dependent manner by upregulating the expression of myocardial transcription factors and its elicitor desmin. Desmin and SPARC interact genetically, forming a positive feedback loop and secreted autocrine and paracrine SPARC negatively affects sparc mRNA expression. Paracrine SPARC rescues cardiomyogenic desmin-haploinsufficiency in cardiac stem cells in a glycosylation-dependent manner, increases desmin expression, the phosphorylation of Smad2 and induces the expression of gata4, nkx2.5 and mef2C. Demonstration that desmin-induced autocrine secretion of SPARC in cardiac stem cells promotes cardiomyogenesis raises the possibility that a physiological function of cardiac stem cells in the adult and aging heart may be the gland-like secretion of factors such as SPARC that modulate age-related and adverse environmental influences and thereby contribute to cardiac homeostasis throughout life.