Autophagic state prospectively identifies facultative stem cells in the intestinal epithelium

Abstract

The intestinal epithelium exhibits a rapid and efficient regenerative response to injury. Emerging evidence supports a model where plasticity of differentiated cells, particularly those in the secretory lineages, contributes to epithelial regeneration upon ablation of injury-sensitive stem cells. However, such facultative stem cell activity is rare within secretory populations. Here, we ask whether specific functional properties predict facultative stem cell activity. We utilize in vivo labeling combined with ex vivo organoid formation assays to evaluate how cell age and autophagic state contribute to facultative stem cell activity within secretory lineages. Strikingly, we find that cell age (time elapsed since cell cycle exit) does not correlate with secretory cell plasticity. Instead, high autophagic vesicle content predicts plasticity and resistance to DNA damaging injury independently of cell lineage. Our findings indicate that autophagic status prior to injury serves as a lineageagnostic marker for the prospective identification of facultative stem cells.

Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential

“…In the intestine, we have recently demonstrated that high AV level prospectively identifies facultative stem cells that contribute to the DNA damage response after ionizing radiation exposure. 46 It remains to be determined whether facultative stem cells marked by high AV level contribute to esophageal response to stressors including 4NQO.

Figure 16 Proposed model.

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Single Cell Analysis of Human Colonoids Exposed to Uranium-Bearing Dust

“…There has been strong evidence that implicated EECs as facultative stem cells that promote plasticity and regeneration of the gut. 88 , 92 However, EEC expansion can also contribute to the rise of small intestinal neuroendocrine tumors. 93 EECs can revert to stem cells following injury with high intensity radiation (12 Gy) that causes massive cell death and ablation of crypt-based stem cells.…”

Autophagy contributes to homeostasis in esophageal epithelium where high autophagic vesicle content marks basal cells with limited proliferation and enhanced self-renewal potential

“…It is further possible that 4NQO may promote a local microenvironment that activates the self-renewal potential of Cyto-ID High cells, similar to our findings in 3D organoids. In the intestine, we have recently demonstrated that high AV level prospectively identifies facultative stem cells that contribute to the DNA damage response following ionizing radiation exposure 44 . It remains to be determined if facultative stem cells marked by high AV level contribute to esophageal response to stressors including 4NQO.…”