Abstract & Authors:展开
The turnover of the intestinal epithelium is driven by multipotent LGR5+ crypt-base columnar cells (CBCs) located at the bottom of crypt zones1 . However, CBCs are lost following injury, such as irradiation2 , but the intestinal epithelium is nevertheless able to recover3 . Thus, a second population of quiescent ‘+4’ cells, or reserve stem cells (RSCs), has previously been proposed to regenerate the damaged intestine4–7 . Although CBCs and RSCs were thought to be mutually exclusive4,8 , subsequent studies have found that LGR5+ CBCs express RSC markers9 and that RSCs were dispensable— whereas LGR5+ cells were essential—for repair of the damaged intestine3 . In addition, progenitors of absorptive enterocytes10, secretory cells11–15 and slow cycling LGR5+ cells16 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+ cells17. 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.
Jeffrey L Wrana,Alex Gregorieff
Arshad Ayyaz,Sandeep Kumar,Bruno Sangiorgi,Bibaswan Ghoshal,Jessica Gosio,Shaida Ouladan,Mardi Fink,Seda Barutcu,Daniel Trcka,Jess Shen,Kin Chan,Jeffrey L Wrana,Alex Gregorieff