USP7 restricts lineage potency in human embryonic stem cells through modulating mTOR activity

Qi Xing; Fei Li; Yao Feng; Huaisong Lin; Aiping Lin; Yanqi Zhang; Cong Zhang; Jiaming Gu; Xue Shi; Zhishuai Zhang; Tiancheng Zhou; Qianyu Chen; Yanling Zhu; Yazhou Cui; Xiaofei Zhang; Bo Feng; Guangjin Pan; Yongli Shan

doi:10.59717/j.xinn-life.2025.100171

The Innovation Life > 2025 Vol. 3 > No. 4 > 100171

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USP7 restricts lineage potency in human embryonic stem cells through modulating mTOR activity

1.
State Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
2.
Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
3.
University of Chinese Academy of Sciences, Beijing 100049, China
4.
Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong SAR 999077, China
5.
Shandong Medicinal Biotechnology Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250012, China
6.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China

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7These authors contributed equally to this work
Corresponding authors: shan_yongli@gibh.ac.cn (Y.S.); pan_guangjin@gibh.ac.cn (G.P.)
Received Date: August 07, 2025

Accepted Date: October 31, 2025

Published Online: November 13, 2025

The Innovation Life 3(4), https://doi.org/10.59717/j.xinn-life.2025.100171 | Cite this article

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. USP7 deficiency enables human embryonic stem cells to self-organize into tri-lineage aggregates autonomously.
  
  USP7 restricts lineage potency by modulating the mTOR signaling-mediated protein synthesis.
  
  The deubiquitinase USP7 constrains mTOR activity via reducing K63-linked polyubiquitination.

ABSTRACT

ABSTRACT

During early embryonic development, totipotent cells undergo cell-autonomous lineage restriction to give rise to extra-embryonic (ExE) lineages, including the trophectoderm (TE). Conventional human embryonic stem cells (hESCs), derived from the inner cell mass (ICM), possess limited ExE potential; However, the underlying intrinsic determinants remain elusive. Here, we demonstrate that deficiency of USP7, a deubiquitinase, releases this lineage restriction in hESCs and enhances their ExE potency. USP7-deficient hESCs exhibit elevated naïve pluripotency characteristics and self-organize into aggregate structures with markerdly enhanced ExE specification. We further show that USP7 constrains protein synthesis in conventional hESCs, which in turn limits their developmental potency. Mechanistically, we identify that USP7 attenuates mTOR activity through modulating K63-linked polyubiquitination in hESCs. Collectively, our findings uncover a cell-intrinsic regulatory mechanism by which USP7 governs mTOR activity to restrict the developmental potency in hESCs.
- USP7 /
- human embryonic stem cells /
- lineage potency restriction /
- mTOR /
- K63-linked polyubiquitination

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Xing Q., Li F., Feng Y., et al. (2025). USP7 restricts lineage potency in human embryonic stem cells through modulating mTOR activity. The Innovation Life 3:100171. https://doi.org/10.59717/j.xinn-life.2025.100171

Xing Q., Li F., Feng Y., et al. (2025). USP7 restricts lineage potency in human embryonic stem cells through modulating mTOR activity. The Innovation Life 3:100171. https://doi.org/10.59717/j.xinn-life.2025.100171

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USP7 restricts lineage potency in human embryonic stem cells through modulating mTOR activity

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USP7 restricts lineage potency in human embryonic stem cells through modulating mTOR activity

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