Tumor necrosis factor alpha induces platelet‐derived growth factor receptor expression in cardiac mesenchymal stem cells that guides their myofibroblast differentiation

Abstract

Heart failure (HF) is a global health problem. Analogous to inflammation, failing hearts also exhibit progressive fibrosis. Stem cells hold significant promise for ischemic heart diseases. However, there has not been clinical success so far. Understanding the effect of failing myocardium on stem cells is thus essential for devising efficient cell-based therapies. In addition to fibroblasts, mesenchymal stem cells (MSCs) can also differentiate into pro-fibrotic myofibroblasts. Platelet derived growth factors (PDGF) and PDGF-receptors (PDGFRs) are known regulators of fibrosis. We have discovered that cardiac MSCs (cMSCs) from failing hearts exhibit increased PDGFRβ (Rβ) expression and PDGFR-dependent myofibroblast differentiation. We hypothesize that inflammatory microenvironment in failing hearts promotes cMSC-Rβ expression and their subsequent myofibroblast differentiation. Wild type mouse cMSCs (Sca1+CD31-DDR2-) when exposed to pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) significantly increased their Rβ-expression that is mediated by JNK and Erk MAPK-activation but not NF-kB activation. More importantly, TNF-induced Rβ-expression in cMSCs is independent of Rβ-promoter transactivation. Evaluation of Rβ-promoter identified a putative CpG island which when deleted significantly increased basal Rβ-promoter activity suggesting role of DNA-methylation in modulating TNF-induced Rβ-expression in cMSCs. DNA-methylation is known to correlate directly with promotor activation and gene expression. Indeed, compared to HF cMSCs (with increased Rβ-expression), CpG island within Rβ-promoter in sham cMSCs (with decreased Rβ-expression) is predominantly methylated, and acute TNF exposure (24h) promotes its de-methylation that correlates with increased Rβ-expression. We conclude that regulating cMSC-localized Rβ expression could therapeutically be used to prevent cMSC-myofibroblast differentiation and attenuate overt fibrotic responses in HF.