Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell

Nature. 2019 May;569(7754):121-125. doi: 10.1038/s41586-019-1154-y. Epub 2019 Apr 24.


The turnover of the intestinal epithelium is driven by multipotent LGR5+ crypt-base columnar cells (CBCs) located at the bottom of crypt zones1. However, CBCs are lost following injury, such as irradiation2, but the intestinal epithelium is nevertheless able to recover3. Thus, a second population of quiescent '+4' cells, or reserve stem cells (RSCs), has previously been proposed to regenerate the damaged intestine4-7. Although CBCs and RSCs were thought to be mutually exclusive4,8, subsequent studies have found that LGR5+ CBCs express RSC markers9 and that RSCs were dispensable-whereas LGR5+ cells were essential-for repair of the damaged intestine3. In addition, progenitors of absorptive enterocytes10, secretory cells11-15 and slow cycling LGR5+ cells16 have been shown to contribute to regeneration whereas the transcriptional regulator YAP1, which is important for intestinal regeneration, was suggested to induce a pro-survival phenotype in LGR5+ cells17. Thus, whether cellular plasticity or distinct cell populations are critical for intestinal regeneration remains unknown. Here we applied single-cell RNA sequencing to profile the regenerating mouse intestine and identified a distinct, damage-induced quiescent cell type that we term the revival stem cell (revSC). revSCs are marked by high clusterin expression and are extremely rare under homoeostatic conditions, yet give rise-in a temporal hierarchy-to all the major cell types of the intestine, including LGR5+ CBCs. After intestinal damage by irradiation, targeted ablation of LGR5+ CBCs, or treatment with dextran sodium sulfate, revSCs undergo a YAP1-dependent transient expansion, reconstitute the LGR5+ CBC compartment and are required to regenerate a functional intestine. These studies thus define a unique stem cell that is mobilized by damage to revive the homoeostatic stem cell compartment and regenerate the intestinal epithelium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Homeostasis
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / metabolism
  • Regeneration / genetics*
  • Regeneration / physiology
  • Sequence Analysis, RNA
  • Single-Cell Analysis*
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • Transcriptome*