Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival

Yang Yang, Maria Gomez, Timothy Marsh, Laura Poillet-Perez, Akshada Sawant, Lei Chen, Noel R. Park, S. RaElle Jackson, Zhixian Hu, Noa Alon, Chen Liu, Jayanta Debnath, Jun Lin Guan, Shawn Davidson, Michael Verzi, Eileen White*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.

Original languageEnglish (US)
Article numbere2202016119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number21
StatePublished - May 24 2022


  • IBD
  • autophagy
  • intestine
  • metabolism
  • stem cells

ASJC Scopus subject areas

  • General


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