Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):466-71. doi: 10.1073/pnas.1118857109. Epub 2011 Dec 21.
The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1(+) ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1(+) ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5(+) ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.
小肠上皮细胞在隐窝肠干细胞（ISCs）的支持下经历快速和连续的再生。Bmi1 和 Lgr5 已被独立鉴定为通过在小鼠中的谱系追踪来标记长寿多能性 ISC；然而，这两个群体之间的功能区别仍未定义。在这里，我们证明 Bmi1 和 Lgr5 在体内标记两个功能不同的 ISC。Lgr5 标记有丝分裂活跃的 ISC，其对经典 Wnt 调节具有极高的敏感性，对稳态再生有很大的贡献，并且可以通过辐射定量消除。相比之下，Bmi1 标记静止的 ISC，对 Wnt 扰动不敏感，对稳态再生贡献较弱，对高剂量辐射损伤有抗性。然而，在照射后，通常静止的 Bmi1(+) ISC 会剧烈增殖，以克隆方式重新填充多个相邻的隐窝和绒毛。分离的单个 Bmi1(+) ISC 的克隆培养产生具有长期自我更新能力的肠上皮球体，产生表达 Lgr5 的细胞，从而在体外建立这两个群体之间的谱系关系。总之，这些数据提供了直接证据，证明 Bmi1 标记静止、损伤诱导的储备 ISC，与 Lgr5(+) ISC 具有显著的功能区别，并支持一种模型，即不同的 ISC 群体促进稳态与损伤诱导的再生。
