TY - JOUR
T1 - Characterization of radioresistant epithelial stem cell heterogeneity in the damaged mouse intestine
AU - Sato, Taku
AU - Sase, Miwako
AU - Ishikawa, Shun
AU - Kajita, Mihoko
AU - Asano, Jumpei
AU - Sato, Toshiro
AU - Mori, Yoshiyuki
AU - Ohteki, Toshiaki
N1 - Funding Information:
We thank H. Kamioka for secretarial support, K. Shiseki and S. Kuroda for technical support. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Stem Cell Aging and Disease” (#15H01508, #17H05635), “Inflammation Cellular Sociology” (#18H05028) from MEXT, Japan (T.O.), by the Mitsubishi Foundation (T.O.), by the Cooperation Program between TMDU and Sony IP&S, Inc. (T.O.), by Nanken-Kyoten (Toshiro. S.), TMDU, and by the Japan Science and Technology Agency, PREST (#JPMJPR13M4, Taku. S.).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-020-64987-1
DO - 10.1038/s41598-020-64987-1
M3 - Article
C2 - 32444673
AN - SCOPUS:85085194108
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 8308
ER -