AGED CARDIAC PATIENTS SHOW IMPAIRED MESENCHYMAL STEM CELL DIFFERENTIATION TO A MYOGENIC PHENOTYPE DUE TO DEPRESSED WNT/beta-CATENIN SIGNALING

Autologous stem cell therapy has not been as effective as forecasted from preclinical studies. Patient age was reported as an important contributing factor. Our goal was to uncover age-dependent mechanisms of stem cell dysfunction and to rejuvenate the aged stem cells. We evaluated bone marrow multipotent mesenchymal stem cells (MSCs) from cardiac patients of different ages. Myogenic differentiation of high-density MSC cultures was induced by exposure to 5-azacytidine. Quantitative real-time PCR was used to identify genes in the WNT/β-catenin signaling network from aged MSCs. Lithium chloride was administered to restore WNT/β-catenin signaling. In response to 5-azacytidine (5-Aza), differentiation was lower in MSCs from aged patients (Fig. A). The transcript levels of CTNNB1, LEF1, FZD8, WNT3A, and SFRP4 were negatively correlated with age, whereas FOSL1, LRP6, and FZD6 were positively correlated with age. At the protein level, nuclear translocation of β-catenin was lower in aged MSCs. However, aged MSCs treated with lithium chloride (LiCl)—to increase the bioavailability of β-catenin during differentiation—recovered the capacity for myogenic differentiation (Fig. B, C) through MEF2C, but failed to do so with the knockdown of β-catenin using siRNA, thus establishing a potential causative role of β-catenin in the age-dependent decline of MSC function from cardiovascular patients. The reduced nuclear β-catenin bioavailability in MSCs from aged patients impaired myogenic differentiation. This deficiency was recoverable in vitro, providing a logical target to improve the function of bone marrow stem cells and their clinical utility in aged patients.