Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Nature. 2019 May;569(7754):121-125. doi: 10.1038/s41586-019-1154-y. Epub 2019 Apr 24.
The turnover of the intestinal epithelium is driven by multipotent LGR5 crypt-base columnar cells (CBCs) located at the bottom of crypt zones. However, CBCs are lost following injury, such as irradiation, but the intestinal epithelium is nevertheless able to recover. Thus, a second population of quiescent '+4' cells, or reserve stem cells (RSCs), has previously been proposed to regenerate the damaged intestine. Although CBCs and RSCs were thought to be mutually exclusive, subsequent studies have found that LGR5 CBCs express RSC markers and that RSCs were dispensable-whereas LGR5 cells were essential-for repair of the damaged intestine. In addition, progenitors of absorptive enterocytes, secretory cells and slow cycling LGR5 cells have been shown to contribute to regeneration whereas the transcriptional regulator YAP1, which is important for intestinal regeneration, was suggested to induce a pro-survival phenotype in LGR5 cells. Thus, whether cellular plasticity or distinct cell populations are critical for intestinal regeneration remains unknown. Here we applied single-cell RNA sequencing to profile the regenerating mouse intestine and identified a distinct, damage-induced quiescent cell type that we term the revival stem cell (revSC). revSCs are marked by high clusterin expression and are extremely rare under homoeostatic conditions, yet give rise-in a temporal hierarchy-to all the major cell types of the intestine, including LGR5 CBCs. After intestinal damage by irradiation, targeted ablation of LGR5 CBCs, or treatment with dextran sodium sulfate, revSCs undergo a YAP1-dependent transient expansion, reconstitute the LGR5 CBC compartment and are required to regenerate a functional intestine. These studies thus define a unique stem cell that is mobilized by damage to revive the homoeostatic stem cell compartment and regenerate the intestinal epithelium.
肠上皮细胞的更新由位于隐窝区底部的多能性 LGR5 隐窝基柱状细胞（CBC）驱动。然而，CBC 在受到损伤后会丢失，例如辐射，但肠道上皮细胞仍然能够恢复。因此，先前曾提出第二种静止的“+4”细胞或储备干细胞（RSC）来再生受损的肠道。尽管 CBC 和 RSC 被认为是相互排斥的，但随后的研究发现 LGR5 CBC 表达 RSC 标记物，并且 RSC 是可有可无的-而 LGR5 细胞对于修复受损的肠道是必不可少的。此外，吸收性肠细胞、分泌细胞和缓慢循环的 LGR5 细胞的祖细胞已被证明有助于再生，而对于肠道再生很重要的转录调节因子 YAP1 被认为可诱导 LGR5 细胞中的存活表型。因此，肠道再生是否需要细胞可塑性或不同的细胞群体尚不清楚。在这里，我们应用单细胞 RNA 测序来分析再生的小鼠肠道，并鉴定出一种独特的、损伤诱导的静止细胞类型，我们将其命名为复苏干细胞（revSC）。revSCs 的特征是高簇蛋白表达，在稳态条件下极为罕见，但在时间层次上可产生肠道的所有主要细胞类型，包括 LGR5 CBC。在通过辐射、靶向消融 LGR5 CBC 或用葡聚糖硫酸钠处理造成肠道损伤后，revSCs 会经历依赖 YAP1 的短暂扩增，重建 LGR5 CBC 区室，并需要其来再生功能性肠道。这些研究因此定义了一种独特的干细胞，它可以通过损伤被动员起来，恢复稳态干细胞区室并再生肠道上皮细胞。
