BCL-xL/BCL2L1 is a critical anti-apoptotic protein that promotes the survival of differentiating pancreatic cells from human pluripotent stem cells
| Autor: | Hyungwon Choi, Xavier Roca, Larry Sai Weng Loo, Andreas Alvin Purnomo Soetedjo, Natasha Hui Jin Ng, Soumita Ghosh, Shawn Hoon, Adrian Kee Keong Teo, Vidhya Gomathi Krishnan, Linh Nguyen, Hwee Hui Lau |
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| Rok vydání: | 2019 |
| Předmět: |
Pluripotent Stem Cells
Cancer Research Immunology bcl-X Protein Stem-cell differentiation Bcl-xL Apoptosis Biology Cell fate determination Article Cellular and Molecular Neuroscience Downregulation and upregulation Gene expression Humans Progenitor cell lcsh:QH573-671 Induced pluripotent stem cell Cell Proliferation lcsh:Cytology Caspase 3 Cell Differentiation Cell Biology Cell biology Pancreatic Neoplasms Proto-Oncogene Proteins c-bcl-2 Differentiation biology.protein Beta cell |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 5, Pp 1-18 (2020) |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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