Rapidly cycling stem cells regenerate the intestine independent of Lgr5high cells

Sheng, X.; Lin, Z.; Lv, C.; Shao, C.; Bi, X.; Deng, M.; Xu, J.; F. Guerrero-Juarez, C.; Li, M.; Wu, X.; Zhao, R.; Liu, X.; Wang, Q.; Nie, Q.; Cui, W.; Gao, S.; Zhang, H.; Liu, Z.; Cong, Y.; Plikus, M. V.; Lengner, C.; Andersen, B.; Ren, F.; Yu, Z.

doi:10.1101/813402

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bioRxiv · 10.1101/813402

Rapidly cycling stem cells regenerate the intestine independent of Lgr5high cells

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Abstract

The +4 cells in intestinal crypts are DNA damage-resistant and contribute to regeneration. However, their exact identity and the mechanism underlying +4 cell-mediated regeneration remain unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1+) are enriched at the +4 position in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1+ cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1+ cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5high radio-sensitive crypt base columnar stem cells (CBCs); they enable fast repopulation of the intestinal epithelium independent of CBCs that are largely depleted after irradiation. Furthermore, relative to CBCs, Msi1+ cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1+ cells are rapidly cycling ISCs that maintain and regenerate the intestinal epithelium.

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Sheng, X., Lin, Z., Lv, C., Shao, C., Bi, X., Deng, M., Xu, J., F. Guerrero-Juarez, C., Li, M., Wu, X., Zhao, R., Liu, X., Wang, Q., Nie, Q., Cui, W., Gao, S., Zhang, H., Liu, Z., Cong, Y., Plikus, M. V., Lengner, C., Andersen, B., Ren, F., Yu, Z.. 2019-10-21. Rapidly cycling stem cells regenerate the intestine independent of Lgr5high cells. https://doi.org/10.1101/813402

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