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.”

Original languageEnglish
Pages (from-to)166-179.e6
JournalDevelopmental cell
Issue number2
StatePublished - Jan 24 2022


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


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