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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / pathology
  • Colitis / prevention & control*
  • Colon / cytology*
  • Colon / physiology
  • Homeostasis
  • Intestine, Small / cytology*
  • Intestine, Small / physiology
  • Keratin-19 / genetics
  • Keratin-19 / metabolism
  • Mice
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Regeneration*
  • Stem Cells / cytology*
  • Stem Cells / physiology

Substances

  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Keratin-19
  • Lgr5 protein, mouse
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Receptors, G-Protein-Coupled