A number of signalling pathways and factors have been shown to regulate pluripotency and self-renewal in embryonic stem cells (ESCs). These include mitogen-activated protein kinase kinase (MEK) and glycogen synthase kinase 3 (Gsk3), inhibitors of which are used to maintain ESCs in culture. Now, Shou-Dong Ye and colleagues report that inhibition of protein kinase D (PKD) using the small molecule inhibitor CID755673 (CID) can promote the maintenance of ESCs. They identify CID in a screen for molecules that promote mouse ESC self-renewal in vitro. Following on from this, they report that dual administration of CID and the MEK inhibitor PD promotes the long-term maintenance of undifferentiated mouse ESCs. The researchers further demonstrate that inhibiting PKD1, PKD2 and PKD3 expression in mouse ESCs using short hairpin RNAs can mimic the self-renewal-promoting effect of CID. In line with this, their analyses of PKD gene expression in ESCs suggest that that upregulation of PKD genes triggers ESC differentiation. Finally, the authors report that PKD inhibition can also promote the self-renewal of human ESCs, partially through activation of the PI3K/AKT signalling pathway. Together, these findings uncover a conserved and novel mechanism that can be leveraged to maintain stemness in mouse and human ESCs.
