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

Author

Listed:
  • 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
    University of Toronto)

  • Shaida Ouladan

    (McGill University and Cancer Research Program, Research Institute of McGill University Health Centre)

  • Mardi Fink

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto)

  • 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
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital)

  • Jeffrey L. Wrana

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Alex Gregorieff

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    McGill University and Cancer Research Program, Research Institute of McGill University Health Centre)

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.

Suggested Citation

  • 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 Gregorief, 2019. "Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell," Nature, Nature, vol. 569(7754), pages 121-125, May.
  • Handle: RePEc:nat:nature:v:569:y:2019:i:7754:d:10.1038_s41586-019-1154-y
    DOI: 10.1038/s41586-019-1154-y
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    Citations

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    Cited by:

    1. Scott R. Tyler & Daniel Lozano-Ojalvo & Ernesto Guccione & Eric E. Schadt, 2024. "Anti-correlated feature selection prevents false discovery of subpopulations in scRNAseq," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Yunpei Xu & Shaokai Wang & Qilong Feng & Jiazhi Xia & Yaohang Li & Hong-Dong Li & Jianxin Wang, 2024. "scCAD: Cluster decomposition-based anomaly detection for rare cell identification in single-cell expression data," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Tsunaki Higa & Yasutaka Okita & Akinobu Matsumoto & Shogo Nakayama & Takeru Oka & Osamu Sugahara & Daisuke Koga & Shoichiro Takeishi & Hirokazu Nakatsumi & Naoki Hosen & Sylvie Robine & Makoto M. Take, 2022. "Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Jina Yun & Simon Hansen & Otto Morris & David T. Madden & Clare Peters Libeu & Arjun J. Kumar & Cameron Wehrfritz & Aaron H. Nile & Yingnan Zhang & Lijuan Zhou & Yuxin Liang & Zora Modrusan & Michelle, 2023. "Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Sara M. Parigi & Ludvig Larsson & Srustidhar Das & Ricardo O. Ramirez Flores & Annika Frede & Kumar P. Tripathi & Oscar E. Diaz & Katja Selin & Rodrigo A. Morales & Xinxin Luo & Gustavo Monasterio & C, 2022. "The spatial transcriptomic landscape of the healing mouse intestine following damage," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Kyung Mok Kim & Anna Mura-Meszaros & Marie Tollot & Murali Shyam Krishnan & Marco Gründl & Laura Neubert & Marco Groth & Alejo Rodriguez-Fraticelli & Arthur Flohr Svendsen & Stefano Campaner & Nico An, 2022. "Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Yi Liu & Efren Reyes & David Castillo-Azofeifa & Ophir D. Klein & Todd Nystul & Diane L. Barber, 2023. "Intracellular pH dynamics regulates intestinal stem cell lineage specification," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Marco Calafiore & Ya-Yuan Fu & Paola Vinci & Viktor Arnhold & Winston Y. Chang & Suze A. Jansen & Anastasiya Egorova & Shuichiro Takashima & Jason Kuttiyara & Takahiro Ito & Jonathan Serody & Susumu N, 2023. "A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Clara Morral & Arshad Ayyaz & Hsuan-Cheng Kuo & Mardi Fink & Ioannis I. Verginadis & Andrea R. Daniel & Danielle N. Burner & Lucy M. Driver & Sloane Satow & Stephanie Hasapis & Reem Ghinnagow & Lixia , 2024. "p53 promotes revival stem cells in the regenerating intestine after severe radiation injury," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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