Int J Biol Sci 2022; 18(9):3562-3575. doi:10.7150/ijbs.71199 This issue

Research Paper

Insulin Directs Dichotomous Translational Regulation to Control Human Pluripotent Stem Cell Survival, Proliferation and Pluripotency

Xiaoxiao Zhou1, Zhili Ren1, Jiaqi Xu1, Chunhao Deng1, Zhaoying Zhang1, Carlos Godoy-Parejo1, Faxiang Xu1, Esther Chi Cheng Huang1, Jiajia Wang2, Zheyu Cai3, Weiwei Liu1,4,5,6, Guang Hu2, Guokai Chen1,4,6✉

1. Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China.
2. Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, RTP, NC 27709, USA.
3. Animal Research Core Facility, Faculty of Health Sciences, University of Macau, Macau SAR, China.
4. Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China.
5. Bioimaging and Stem Cell Core Facility, Faculty of Health Sciences, University of Macau, Macau SAR, China.
6. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Zhou X, Ren Z, Xu J, Deng C, Zhang Z, Godoy-Parejo C, Xu F, Huang ECC, Wang J, Cai Z, Liu W, Hu G, Chen G. Insulin Directs Dichotomous Translational Regulation to Control Human Pluripotent Stem Cell Survival, Proliferation and Pluripotency. Int J Biol Sci 2022; 18(9):3562-3575. doi:10.7150/ijbs.71199. Available from https://www.ijbs.com/v18p3562.htm

File import instruction

Abstract

Graphic abstract

Insulin is essential for diverse biological processes in human pluripotent stem cells (hPSCs). However, the underlying mechanism of insulin's multitasking ability remains largely unknown. Here, we show that insulin controls hPSC survival and proliferation by modulating RNA translation via distinct pathways. It activates AKT signaling to inhibit RNA translation of pro-apoptotic proteins such as NOXA/PMAIP1, thereby promoting hPSC survival. At the same time, insulin acts via the mTOR pathway to enhance another set of RNA translation for cell proliferation. Consistently, mTOR inhibition by rapamycin results in eIF4E phosphorylation and translational repression. It leads to a dormant state with sustained pluripotency but reduced cell growth. Together, our study uncovered multifaceted regulation by insulin in hPSC survival and proliferation, and highlighted RNA translation as a key step to mediate mitogenic regulation in hPSCs.

Keywords: Cell Survival, Insulin, AKT, NOXA/PMAIP1, mTOR, eIF4E, Pluripotency, Proliferation, Translation, Human pluripotent stem cell (hPSC)