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EMBO J. 2019 Feb 15;38(4). pii: e99984. doi: 10.15252/embj.201899984. Epub 2019 Jan 11.

Atoh1+ secretory progenitors possess renewal capacity independent of Lgr5+ cells during colonic regeneration.

Author information

1
Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, USA.
2
Department of Medicine, University of Western Ontario, London, ON, Canada.
3
Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
4
Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada.
5
Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
6
Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, USA ophir.klein@ucsf.edu sasfaha2@uwo.ca.
7
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
8
Department of Medicine, University of Western Ontario, London, ON, Canada ophir.klein@ucsf.edu sasfaha2@uwo.ca.

Abstract

During homeostasis, the colonic epithelium is replenished every 3-5 days by rapidly cycling Lgr5 + stem cells. However, various insults can lead to depletion of Lgr5 + stem cells, and colonic epithelium can be regenerated from Lgr5-negative cells. While studies in the small intestine have addressed the lineage identity of the Lgr5-negative regenerative cell population, in the colon this question has remained unanswered. Here, we set out to identify which cell(s) contribute to colonic regeneration by performing genetic fate-mapping studies of progenitor populations in mice. First, using keratin-19 (Krt19) to mark a heterogeneous population of cells, we found that Lgr5-negative cells can regenerate colonic crypts and give rise to Lgr5 + stem cells. Notch1 + absorptive progenitor cells did not contribute to epithelial repair after injury, whereas Atoh1 + secretory progenitors did contribute to this process. Additionally, while colonic Atoh1 + cells contributed minimally to other lineages during homeostasis, they displayed plasticity and contributed to epithelial repair during injury, independent of Lgr5 + cells. Our findings suggest that promotion of secretory progenitor plasticity could enable gut healing in colitis.

KEYWORDS:

Atoh1; Krt19; Notch1; colitis; stem cells

PMID:
30635334
PMCID:
PMC6376326
[Available on 2020-02-15]
DOI:
10.15252/embj.201899984

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