Loo, L.S.W., Soetedjo, A.A.P., Lau, H.H. et al. BCL-xL/BCL2L1 is a critical anti-apoptotic protein that promotes the survival of differentiating pancreatic cells from human pluripotent stem cells. Cell Death Dis 11, 378 (2020). https://doi.org/10.1038/s41419-020-2589-7
The differentiation of human pluripotent stem cells into pancreatic cells involves cellular proliferation and apoptosis during cell fate transitions. However, their implications for establishing cellular identity are unclear. Here, we profiled the expression of BCL-2 family of proteins during pancreatic specification and observed an upregulation of BCL-xL, downregulation of BAK and corresponding downregulation of cleaved CASP3 representative of apoptosis. Experimental inhibition of BCL-xL reciprocally increased apoptosis and resulted in a decreased gene expression of pancreatic markers despite a compensatory increase in anti-apoptotic protein BCL-2. RNA-Seq analyses then revealed a downregulation of multiple metabolic genes upon inhibition of BCL-xL. Follow-up bioenergetics assays revealed broad downregulation of both glycolysis and oxidative phosphorylation when BCL-xL was inhibited. Early perturbation of BCL-xL during pancreatic specification also had subsequent detrimental effects on the formation of INS+ pancreatic beta-like cells. In conclusion, the more differentiated pancreatic progenitors are dependent on anti-apoptotic BCL-xL for survival, whereas the less differentiated pancreatic progenitors that survived after WEHI-539 treatment would exhibit a more immature phenotype. Therefore, modulation of the expression level of BCL-xL can potentially increase the survival and robustness of pancreatic progenitors that ultimately define human pancreatic beta cell mass and function.
L.S.W.L. and L.N. are supported by the A*STAR Graduate Academy (A*GA). A.K.K.T. is supported by the Institute of Molecular and Cell Biology (IMCB), A*STAR, NMRC Open Fund-Young Individual Research Grant (OF-YIRG) OFYIRG16may014, A*STAR ETPL Gap Funding ETPL/18-GAP005-R20H, Lee Foundation Grant SHTX/LFG/002/2018, Skin Innovation Grant SIG18011, NMRC OF-LCG/DYNAMO, FY2019 SingHealth
Duke-NUS Surgery Academic Clinical Program Research Support Program Grant, the Precision Medicine and Personalized Therapeutics Joint Research Grant 2019, the Industry Alignment Fund – Industry Collaboration Project (IAFICP) and the 2nd A*STAR-AMED Joint Grant Call 192B9002.