Volume 36, No 3, Mar 2026

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 36 Issue 3, March 2026: 219-232

ORIGINAL ARTICLES

Asymmetric division in a two-cell-like state rejuvenates embryonic stem cells

Xinyi Wang^1,2,† , Hong Fu^2,3,† , Qingyang Sun^2,3,4,† , Boyan Huang^1,2,† , Zhe Xu^1,2,† , Xuzhao Zhai^2,5 , Chuncao Deng^2,6 , Laru Peng^1,2 , Mengdan Zhang^1,2 , Tianran Peng^1,2 , An Gong^1,2 , Jiasui Liu^1,2,8 , Zhengzhi Zou⁴ , Guangjin Pan⁷ , Jiekai Chen⁷ , Guangming Wu² , Man Zhang^1,2,* , Mingwei Min^1,2,*

¹GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, Guangdong, China
²Guangzhou National Laboratory, Guangzhou, Guangdong, China
³School of Life Science and Technology, ShanghaiTech University, Shanghai, China
⁴MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
⁵Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
⁶Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
⁷Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
⁸Present address: Department of Molecular Sociology, Max Planck Institute of Biophysics, Frankfurt am Main, Germany
^†These authors contributed equally: Xinyi Wang, Hong Fu, Qingyang Sun, Boyan Huang, Zhe Xu
Correspondence: Man Zhang(zhang_man@gzlab.ac.cn)Mingwei Min(min_mingwei@gzlab.ac.cn)

A fundamental question in biology is whether all cells age. Embryonic stem cells (ESCs) defy the norm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortality remain unresolved. Using long-term live-cell imaging to follow the fates of single ESCs, we show that ESC lineage renewal is achieved through sporadic entry into a state characterized by the expression of two-cell embryo-specific markers. During this state, cells undergo asymmetric fate divisions, enriching accumulated DNA damage into one daughter lineage that is destined for elimination, while producing a second lineage that reverts to the pluripotent state. Importantly, the latter lineage exhibits signs of rejuvenation, including reduced DNA damage and enhanced chimeric efficiency. These findings underscore the crucial role of asymmetric cell division in maintaining the long-term health of the ESC lineage against mounting damage within individual cells and provide a potential model for studying cellular aging and rejuvenation in mammalian cells.

https://doi.org/10.1038/s41422-026-01221-z

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