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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.

2019-10-21 cell biology
10.1101/813402 bioRxiv
Show 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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