Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration
Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration
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DOI：
10.1038/s41467-019-14258-z
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发表时间：
2020-01-24
影响因子：
16.6
通讯作者：
Denning, Timothy L.
中科院分区：
文献类型：
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作者：
Abo, Hirohito;Chassaing, Benoit;Denning, Timothy L.
肠道微生物区系及其代谢产物在调节肠道内环境平衡方面起着重要作用。然而，早期生命微生物区系对肠道发育的影响仍然不完全清楚。在这里，我们证明了无菌(GF)小鼠与断奶时无特定病原体(SPF)小鼠的共居(ExGF)导致肠道基因表达的改变。我们的结果显示，一个高度差异表达的基因，红系分化调节因子-1(Erdr1)，在SPF小鼠的发育过程中被诱导，而不是在GF或exGF小鼠中诱导，并定位于Lgr5(+)干细胞和传递扩增(TA)细胞。Erdr1的功能是在上皮细胞中诱导Wnt信号，促进Lgr5(+)干细胞的扩增，并促进肠道器官生长。此外，Erdr1在体外加速划痕愈合，增加体内辐射损伤后Lgr5(+)肠道干细胞的再生，并促进葡聚糖硫酸钠(DSS)诱导的结肠损伤的恢复。总而言之，我们的发现表明，早期生命微生物区系控制Erdr1介导的肠上皮细胞增殖和再生，以应对粘膜损伤。
Gut microbiota and their metabolites are instrumental in regulating intestinal homeostasis. However, early-life microbiota associated influences on intestinal development remain incompletely understood. Here we demonstrate that co-housing of germ-free (GF) mice with specific-pathogen free (SPF) mice at weaning (exGF) results in altered intestinal gene expression. Our results reveal that one highly differentially expressed gene, erythroid differentiation regulator-1 (Erdr1), is induced during development in SPF but not GF or exGF mice and localizes to Lgr5(+) stem cells and transit amplifying (TA) cells. Erdr1 functions to induce Wnt signaling in epithelial cells, increase Lgr5(+) stem cell expansion, and promote intestinal organoid growth. Additionally, Erdr1 accelerates scratch-wound closure in vitro, increases Lgr5(+) intestinal stem cell regeneration following radiation-induced injury in vivo, and enhances recovery from dextran sodium sulfate (DSS)-induced colonic damage. Collectively, our findings indicate that early-life microbiota controls Erdr1-mediated intestinal epithelial proliferation and regeneration in response to mucosal damage.