Gfi1-expressing Paneth cells revert to stem cells following intestinal injury

Chen, M.-S.; Lo, Y.-H.; Butkus, J.; Zou, W.; Tseng, Y.-J.; Jen, H.-I.; Patel, S.; Groves, A.; Estes, M.; Sahin, E.; Frey, M.; Dempsey, P.; Shroyer, N.

doi:10.1101/364133

bioRxiv · 10.1101/364133

Gfi1-expressing Paneth cells revert to stem cells following intestinal injury

Chen, M.-S.·Lo, Y.-H.·Butkus, J.·Zou, W.·Tseng, Y.-J.·Jen, H.-I.·Patel, S.·Groves, A.·Estes, M.·Sahin, E.·Frey, M.·Dempsey, P.·Shroyer, N.

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Abstract

BackgroundAimChemotherapy drugs harm rapidly dividing normal healthy cells such as those lining the gastrointestinal tract, causing morbidity and mortality that complicates medical treatment modalities. Growth Factor-Independent 1 (GFI1) is a zinc finger transcriptional repressor implicated in the differentiation of secretory precursors into Paneth and goblet cells in the intestinal epithelium. We hypothesize that stimulating the reversion of Gfi1+ secretory cells into stem cells will improve intestinal epithelial regeneration and mitigate injury.\n\nMethodsGfi1 reporter mice (Gfi1cre/+; ROSA26 LSL-YFP) were treated with Doxorubicin, radiation, anti-CD3 antibody, and rotavirus to induce intestinal injury. Mice and intestinal organoids (enteroids) were used to investigate cellular repair mechanisms following injury.\n\nResultsUnder homeostatic conditions, Gfi1-lineage cells are Paneth and goblet cells, which were non-proliferative and not part of the stem cell pool. After injury, Gfi1+ secretory cells can re-enter the cell cycle and give rise to all cell lineages of the intestinal epithelium including stem cells. Reversion of Gfi1-lineage cells was observed in other injury model systems, including irradiation and anti-CD3 treatment, but not in ISC-sparing rotavirus infection. Our results also demonstrated that PI3kinase/AKT activation improved cell survival, and elevated WNT signaling increased the efficiency of Gfi1+ cell reversion upon injury.\n\nConclusionsThese findings indicate that Gfi1+ secretory cells display plasticity and reacquire stemness following severe damage. Moreover, PI3kinase/AKT and WNT are key regulators involved in injury-induced regeneration. Our studies identified potential therapeutic intervention strategies to mitigate the adverse effects of chemotherapy-induced damage to normal tissues and improve the overall effectiveness of cancer chemotherapy.

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Chen, M.-S., Lo, Y.-H., Butkus, J., Zou, W., Tseng, Y.-J., Jen, H.-I., Patel, S., Groves, A., Estes, M., Sahin, E., Frey, M., Dempsey, P., Shroyer, N.. 2018-07-16. Gfi1-expressing Paneth cells revert to stem cells following intestinal injury. https://doi.org/10.1101/364133

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