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在受损的小鼠肠道中,辐射抗性上皮干细胞异质性的表征。

Characterization of radioresistant epithelial stem cell heterogeneity in the damaged mouse intestine.

机构信息

Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.

PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan.

出版信息

Sci Rep. 2020 May 22;10(1):8308. doi: 10.1038/s41598-020-64987-1.

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 Sca1Lgr5-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 CD81Sca1 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.

摘要

小肠具有强大的再生能力,各种细胞类型在损伤后的上皮再生过程中充当“起源细胞”。然而,每个群体对再生的贡献程度尚不清楚。通过谱系追踪,我们发现 Lgr5 表达细胞的衍生物包含辐射抗性肠干细胞(ISCs),这些细胞对于辐射损伤后的肠道上皮再生至关重要。单细胞 qRT-PCR 分析表明,损伤肠道中存活的 Lgr5 表达细胞衍生物具有显著的异质性,并且 YAP 靶基因 Sca1 的表达水平与其“干性”呈负相关,这表明存活隐窝上皮细胞中的 YAP/Wnt 信号平衡决定了对上皮再生的细胞贡献。Sca1Lgr5 衍生物的单细胞 RNA 测序表明,四跨膜蛋白家族成员 CD81 的表达与 ISC 和增殖相关基因的表达密切相关。与这些发现一致的是,类器官形成能力仅限于损伤隐窝上皮细胞中 CD81Sca1 亚群内。损伤肠道中辐射抗性上皮干细胞异质性的表征可能有助于胃肠道疾病的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92c/7244543/fc53f72a1582/41598_2020_64987_Fig1_HTML.jpg

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