In this study, we explored the mechanism of Arrb2 mediated Sca-1+ CSC differentiation, and found β-arrestin2/miR-155/GSK3β pathway regulates transition of 5′-azacytizine-induced Sca-1+ cells to cardiomyocytes, which might be a new target for the treatment of heart disease. Here, ARRB2 is linked to heart disorder.