Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell
Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell
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DOI：
10.1038/s41586-019-1154-y
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发表时间：
2019-05-02
期刊：
影响因子：
64.8
通讯作者：
Gregorieff, Alex
中科院分区：
文献类型：
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作者：
Ayyaz, Arshad;Kumar, Sandeep;Gregorieff, Alex
肠上皮的更新由位于隐窝区底部的多能LGR 5（+）隐窝基底柱状细胞（CBC）驱动（1）。然而，CBCs在损伤后丢失，例如辐射（2），但肠上皮仍然能够恢复（3）。因此，第二群静止的“+4”细胞，或储备干细胞（RSC），先前已提出再生受损的肠道（4-7）。虽然CBCs和RSC被认为是相互排斥的（4，8），但随后的研究发现LGR 5（+）CBCs表达RSC标志物（9），并且RSC是可分配的-而LGR 5（+）细胞是修复受损肠道所必需的（3）。此外，已显示吸收性肠上皮细胞（10）、分泌细胞（11-15）和慢循环LGR 5（+）细胞（16）的祖细胞有助于再生，而对肠再生重要的转录调节因子YAP 1被认为在LGR 5（+）细胞中诱导促存活表型（17）。因此，细胞可塑性或不同的细胞群是否对肠再生至关重要仍然是未知的。在这里，我们应用单细胞RNA测序来分析再生小鼠肠，并确定了一种独特的，损伤诱导的静止细胞类型，我们称之为复兴干细胞（revSC）。revSC以聚集蛋白高表达为标志，在恒压条件下极其罕见，但肠道所有主要细胞类型（包括LGR 5（+）CBC）的时间层次结构均有所上升。在通过辐射、LGR 5（+）CBC靶向消融或用葡聚糖硫酸钠治疗造成肠损伤后，revSC经历YAP 1依赖性瞬时扩增，重建LGR 5（+）CBC隔室，并需要再生功能性肠。因此，这些研究定义了一种独特的干细胞，它被损伤动员，以恢复稳态干细胞区室并再生肠上皮。
The turnover of the intestinal epithelium is driven by multipotent LGR5(+) crypt-base columnar cells (CBCs) located at the bottom of crypt zones(1). However, CBCs are lost following injury, such as irradiation(2), but the intestinal epithelium is nevertheless able to recover(3). Thus, a second population of quiescent '+4' cells, or reserve stem cells (RSCs), has previously been proposed to regenerate the damaged intestine(4-7). Although CBCs and RSCs were thought to be mutually exclusive(4,8), subsequent studies have found that LGR5(+) CBCs express RSC markers(9) and that RSCs were dispensable-whereas LGR5(+) cells were essential-for repair of the damaged intestine(3). In addition, progenitors of absorptive enterocytes(10), secretory cells(11-15) and slow cycling LGR5(+) cells(16) 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(17). 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.