Dormant Intestinal Stem Cells Are Regulated by PTEN and Nutritional Status

• Dormant stem cells (d-ISCs) contribute to intestinal regeneration after fasting
• Decreased nutrients lead to transient PTEN inhibition and increased d-ISC numbers
• Cell-autonomous activation of PI3K→AKT→mTORC1 signaling mediates d-ISC response
• PTEN is essential for d-ISC maintenance and intestinal regeneration

SummaryThe cellular and molecular mechanisms underlying adaptive changes to physiological stress within the intestinal epithelium remain poorly understood. Here, we show that PTEN, a negative regulator of the PI3K→AKT→mTORC1-signaling pathway, is an important regulator of dormant intestinal stem cells (d-ISCs). Acute nutrient deprivation leads to transient PTEN phosphorylation within d-ISCs and a corresponding increase in their number. This release of PTEN inhibition renders d-ISCs functionally poised to contribute to the regenerative response during re-feeding via cell-autonomous activation of the PI3K→AKT→mTORC1 pathway. Consistent with its role in mediating cell survival, PTEN is required for d-ISC maintenance at baseline, and intestines lacking PTEN have diminished regenerative capacity after irradiation. Our results highlight a PTEN-dependent mechanism for d-ISC maintenance and further demonstrate the role of d-ISCs in the intestinal response to stress.

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