Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell

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 () and Alex Gregorieff ()
Additional contact information
Arshad Ayyaz: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Sandeep Kumar: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Bruno Sangiorgi: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Bibaswan Ghoshal: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Jessica Gosio: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Shaida Ouladan: McGill University and Cancer Research Program, Research Institute of McGill University Health Centre
Mardi Fink: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Seda Barutcu: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Daniel Trcka: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Jess Shen: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Kin Chan: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Jeffrey L. Wrana: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Alex Gregorieff: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital

Nature, 2019, vol. 569, issue 7754, 121-125

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1154-y

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