Acidic pH transiently prevents the silencing of self-renewal and dampens microRNA function in embryonic stem cells

Wenting Guo; Shaohua Wang; Xiaoshan Zhang; Ming Shi; Feifei Duan; Jing Hao; Kaili Gu; Li Quan; Yixia Wu; Zhiyong Liang; Yangming Wang

doi:10.1016/j.scib.2021.03.005

Acidic pH transiently prevents the silencing of self-renewal and dampens microRNA function in embryonic stem cells

Sci Bull (Beijing). 2021 Jul 15;66(13):1319-1329. doi: 10.1016/j.scib.2021.03.005. Epub 2021 Mar 10.

Authors

Wenting Guo¹, Shaohua Wang², Xiaoshan Zhang², Ming Shi², Feifei Duan², Jing Hao², Kaili Gu², Li Quan², Yixia Wu², Zhiyong Liang³, Yangming Wang⁴

Affiliations

¹ Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China. Electronic address: wtcandy@126.com.
² Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
³ Department of Pathology, Molecular Pathology Research Centre, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
⁴ Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China. Electronic address: yangming.wang@pku.edu.cn.

PMID: 36654154
DOI: 10.1016/j.scib.2021.03.005

Abstract

Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells. However, little is known about its regulatory roles in gene expression and cell fate determination. Here, we confirm that glycolytic metabolism and lactate production decrease during the differentiation of mouse embryonic stem cells (mESCs). Importantly, acidic pH due to lactate accumulation can transiently prevent the silencing of mESC self-renewal in differentiation conditions. Furthermore, acidic pH partially blocks the differentiation of human ESCs (hESCs). Mechanistically, acidic pH downregulates AGO1 protein and de-represses a subset of mRNA targets of miR-290/302 family of microRNAs which facilitate the exit of naive pluripotency state in mESCs. Interestingly, AGO1 protein is also downregulated by acidic pH in cancer cells. Altogether, this study provides insights into the potential function and underlying mechanism of acidic pH in pluripotent stem cells (PSCs).

Keywords: Acidic pH; Embryonic stem cells; Glycolysis; Lactate; Pluripotency.