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Abstract
The small intestine has a robust regenerative capacity, and various cell types serve as “cells-of-origin” in the epithelial regeneration process after injury. However, how much each population contributes to regeneration remains unclear. Using lineage tracing, we found that Lgr5-expressing cell derivatives contained radioresistant intestinal stem cells (ISCs) crucial for epithelial regeneration in the damaged intestine after irradiation. Single-cell qRT-PCR analysis showed that surviving Lgr5-expressing cell derivatives in the damaged intestine are remarkably heterogeneous, and that the expression levels of a YAP-target gene Sca1 were inversely correlated with their “stemness”, suggesting that the YAP/Wnt signal balance in surviving crypt epithelial cells determines the cellular contribution to epithelial regeneration. Single-cell RNA sequencing of Sca1–Lgr5-derivatives revealed that expression of a tetraspanin family member CD81 correlated well with the expression of ISC- and proliferation-related genes. Consistent with these findings, organoid-forming ability was confined to the CD81hiSca1– fraction within the damaged crypt epithelial cells. Characterization of radioresistant epithelial stem cell heterogeneity in the damaged intestine may contribute to therapeutic strategies for gastrointestinal diseases.
Highlights
The small intestine has a robust regenerative capacity, and various cell types serve as “cells-of-origin” in the epithelial regeneration process after injury
About 72.3 ± 10.6% of the recovered Lgr5hi intestinal stem cells (ISCs) were positive for tdTomato, indicating that most of the regenerated Lgr5hi ISCs originated from the previous Lgr5hi ISCs (Fig. 2C,D)
Consistent with this finding, another reporter line Lgr5ki: Rosa26-lsl-LacZ mice, in which the Lgr5hi cells express β-galactosidase after tamoxifen administration, showed that the Lgr5hi ISCs had substantially supplied the villus epithelial cells observed 2 weeks after irradiation (Fig. 2E,F). These results show that the Lgr5hi ISCs include the cellular origin of the whole epithelium regeneration occurring upon total body irradiation (TBI)
Summary
The small intestine has a robust regenerative capacity, and various cell types serve as “cells-of-origin” in the epithelial regeneration process after injury. We found that Lgr5-expressing cell derivatives contained radioresistant intestinal stem cells (ISCs) crucial for epithelial regeneration in the damaged intestine after irradiation. Single-cell RNA sequencing of Sca1–Lgr5-derivatives revealed that expression of a tetraspanin family member CD81 correlated well with the expression of ISC- and proliferation-related genes. Consistent with these findings, organoid-forming ability was confined to the CD81hiSca1– fraction within the damaged crypt epithelial cells. Using a combination of genetic lineage tracing, single-cell gene expression profiling, and organoid-formation assays, we characterized the heterogeneity of epithelial stem cells in the tmd.ac.jp www.nature.com/scientificreports/. In genetically unmodified mice, we confirmed that the CD81hiSca1− cell fraction in the damaged intestine is the important source for regeneration
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