Conclusions
These results demonstrate that activation of ARs, particularly of α1 -ARs, promoted miPSC differentiation into cardiac lineages via MEK-ERK1/2 signalling.
Methods
Murine-induced pluripotent stem cells (miPSCs) were cultured in hanging drops to form embryoid bodies, cells of which were then differentiated into cardiomyocytes. To determine whether ARs regulated miPSC differentiation into cardiac lineages, effects of the AR agonist, epinephrine (EPI), on miPSC differentiation and underlying signalling mechanisms, were evaluated.
Results
Treatment with EPI, robustly enhanced miPSC cardiac differentiation, as indicated by increased expression levels of cardiac-specific markers, GATA4, Nkx2.5 and Tnnt2. Although β-AR signalling is the foremost signalling pathway in cardiomyocytes, EPI-enhanced cardiac differentiation depended more on α-AR signalling than β-AR signalling. In addition, selective activation of α1 -AR signalling with specific agonists induced vigorous cardiomyocyte differentiation, whereas selective activation of α2 - or β-AR signalling induced no or less differentiation, respectively. EPI- and α1 -AR-dependent cardiomyocyte differentiation from miPSCs occurred through specific promotion of CPC proliferation via the MEK-ERK1/2 pathway and regulation of miPS cell-cycle progression. Conclusions: These results demonstrate that activation of ARs, particularly of α1 -ARs, promoted miPSC differentiation into cardiac lineages via MEK-ERK1/2 signalling.