期刊
CELL REPORTS
卷 21, 期 9, 页码 2571-2584出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.10.118
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资金
- Cancer Prevention and Research Institute of Texas [RP140563]
- NIH [CA193297-01, CA098258]
- Department of Defense [CA140572]
- Duncan Family Institute for Cancer Prevention and Risk Assessment grant [IRG-08-061-01]
- Center for Stem Cell and Developmental Biology Transformative grant (MD Anderson Cancer Center)
- Institutional Research grant (MD Anderson Cancer Center)
- New Faculty Award [CA016672]
- Metastasis Research Center grant (MD Anderson Cancer Center)
- MD Anderson Cancer Center [CA016672]
Fine control of stem cell maintenance and activation is crucial for tissue homeostasis and regeneration. However, the mechanism of quiescence exit of Tert(+) intestinal stem cells (ISCs) remains unknown. Employing a Tert knockin (Tert(TCE/+)) mouse model, we found that Tert(+) cells are long-term label-retaining self-renewing cells, which are partially distinguished from the previously identified +4 ISCs. Tert(+) cells become mitotic upon irradiation (IR) injury. Conditional ablation of Tert(+) cells impairs IR-induced intestinal regeneration but not intestinal homeostasis. Upon IR injury, Wnt signaling is specifically activated in Tert(+) cells via the ROS-HIFs-transactivated Wnt2b signaling axis. Importantly, conditional knockout of beta-catenin/Ctnnb1 in Tert(+) cells undermines IR-induced quiescence exit of Tert(+) cells, which subsequently impedes intestinal regeneration. Our results that Wnt-signaling-induced activation of Tert(+) ISCs is indispensable for intestinal regeneration unveil the underlying mechanism for how Tert(+) stem cells undergo quiescence exit upon tissue injury.
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