Adaptive differentiation promotes intestinal villus recovery

Dev Cell. 2022 Jan 24;57(2):166-179.e6. doi: 10.1016/j.devcel.2021.12.012. Epub 2022 Jan 10.

Abstract

Loss of differentiated cells to tissue damage is a hallmark of many diseases. In slow-turnover tissues, long-lived differentiated cells can re-enter the cell cycle or transdifferentiate to another cell type to promote repair. Here, we show that in a high-turnover tissue, severe damage to the differentiated compartment induces progenitors to transiently acquire a unique transcriptional and morphological postmitotic state. We highlight this in an acute villus injury model in the mouse intestine, where we identified a population of progenitor-derived cells that covered injured villi. These atrophy-induced villus epithelial cells (aVECs) were enriched for fetal markers but were differentiated and lineage committed. We further established a role for aVECs in maintaining barrier integrity through the activation of yes-associated protein (YAP). Notably, loss of YAP activity led to impaired villus regeneration. Thus, we define a key repair mechanism involving the activation of a fetal-like program during injury-induced differentiation, a process we term "adaptive differentiation."

Keywords: Hippo; YAP; adaptive differentiation; enteropathy; injury-repair; intestine; poly(I:C); regeneration; single-cell RNA sequencing; villus atrophy.

Publication types

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

MeSH terms

  • Adaptation, Biological / physiology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle
  • Cell Cycle Proteins / metabolism
  • Cell Dedifferentiation / genetics
  • Cell Dedifferentiation / physiology*
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Epithelial Cells / metabolism
  • Female
  • Intestinal Mucosa / injuries
  • Intestinal Mucosa / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Phosphoproteins / metabolism
  • Regeneration
  • Signal Transduction / physiology
  • Stem Cells / cytology
  • Wound Healing / physiology*
  • YAP-Signaling Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • YAP-Signaling Proteins
  • Yap1 protein, mouse