Title: Long-Term Culture Captures Injury-Repair Cycles of Colonic Stem Cells
Author: Yi Wang, I-Ling Chiang, Takahiro E. Ohara, Satoru Fujii, Jiye Cheng, Brian D. Muegge, Aaron Ver Heul, Nathan D. Han, Qiuhe Lu, Shanshan Xiong, Feidi Chen, Chin-Wen Lai, Hana Janova, Renee Wu, Charles E. Whitehurst, Kelli L. VanDussen, Ta-Chiang Liu, Jeffrey I. Gordon, L. David Sibley, Thaddeus S. Stappenbeck
Issue&Volume: November 07, 2019
Abstract:The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hopx+ colitis-associated regenerative stem cell (CARSC) population that functionally contributes to mucosal repair in mouse models of colitis. Hopx+ CARSCs, enriched for fetal-like markers, transiently arose from hypertrophic crypts known to facilitate regeneration. Importantly, we established a long-term, self-organizing two-dimensional (2D) epithelial monolayer system to model the regenerative properties and responses of Hopx+ CARSCs. This system can reenact the “homeostasis-injury-regeneration” cycles of epithelial alterations that occur in vivo. Using this system, we found that hypoxia and endoplasmic reticulum stress, insults commonly present in inflammatory bowel diseases, mediated the cyclic switch of cellular status in this process.