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. 2025 Aug 18;60(16):2177-2191.e5.
doi: 10.1016/j.devcel.2025.03.014. Epub 2025 Apr 21.

Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling

Nicholas R Smith  1 , Nicole R Giske  1 , Sidharth K Sengupta  1 , Patrick Conley  2 , John R Swain  1 , Ashvin Nair  1 , Kathryn L Fowler  3 , Christopher Klocke  2 , Yeon Jung Yoo  1 , Ashley N Anderson  1 , Nasim Sanati  2 , Kristof Torkenczy  4 , Andrew C Adey  5 , Jared M Fischer  6 , Guanming Wu  7 , Melissa H Wong  8
Affiliations

Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling

Nicholas R Smith et al. Dev Cell. .

Abstract

Intestinal epithelial development and homeostasis critically rely upon balanced stem cell proliferation, involving slow-cycling/label-retaining and active-cycling/canonical Wnt-dependent intestinal stem cell (ISC) subtypes. ISC regulation during development remains poorly understood but has important implications for establishing key mechanisms governing tissue maintenance. Herein, we identify Bmi1+ cells as functional stem cells present in early murine intestinal development, prior to Lgr5-expressing ISCs. Lineage tracing and single-cell RNA sequencing identify that Bmi1+ ISCs can trace to Lgr5+ ISCs and other differentiated lineages. Initially highly proliferative, Bmi1+ ISCs transition to slow-cycling states as Lgr5+ ISCs emerge. Non-canonical Wnt signaling regulates the proliferative Bmi1+ cell state. These findings highlight the dynamic interplay between stem cell populations and the opposing Wnt pathways that govern proliferation-ultimately having implications for tissue development, homeostasis, regeneration, and tumorigenesis. Understanding these fundamental developmental mechanisms is critical for understanding adult intestinal maintenance.

Keywords: Bmi1; Wnt signaling; development; intestinal stem cell.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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