Autophagy in PDGFRA mesenchymal cells is required for intestinal homeostasis and mammalian survival.

Macroautophagy/autophagy defects are a risk factor for inflamatory bowel disease (IBD), but the mechanism remains unclear. We previously demonstrated that conditional whole-body deletion of the essential (autophagy related 7) gene in adult mice () causes specific tissue damage and shortens lifespan to three months primarily due to neurodegeneration with surprisingly no disturbing effects on the intestine. In contrast, we recently found that conditional whole-body deletion of other essential autophagy genes, or (), cause death within five days due to rapid inhibition of autophagy, elimination of intestinal stem cells, and loss of barrier function in the ileum. mice lose PDGFRA/PDGFRα mesenchymal cells (PMCs) and WNT signaling essential for stem cell renewal. Depletion of aspartate and nucleotides in ileum was revealed by novel mass-spectrometry imaging (MALDI-MSI), consistent with metabolic insufficiency underlying PMCs loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss because gradual whole-body deletion extends lifespan, phenocopying deletion of or . Therefore, we established that autophagy is required for ileum PMC metabolism, stem cell maintenance and mammalian survival. PMC loss caused by autophagy deficiency may therefore contribute to IBD.