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  3. p57Kip2 imposes the reserve stem cell state of gastric chief cells

p57Kip2 imposes the reserve stem cell state of gastric chief cells

  • Cell Stem Cell. 2022 May 5;29(5):826-839.e9. doi: 10.1016/j.stem.2022.04.001.
Ji-Hyun Lee 1,  Somi Kim 2,  Seungmin Han 3,  Jimin Min 4,  Brianna Caldwell 4,  Aileen-Diane Bamford 1,  Andreia Sofia Batista Rocha 1,  JinYoung Park 1,  Sieun Lee 1,  Szu-Hsien Sam Wu 1,  Heetak Lee 1,  Juergen Fink 5,  Sandra Pilat-Carotta 1,  Jihoon Kim 6,  Manon Josserand 5,  Réka Szep-Bakonyi 1,  Yohan An 7,  Young Seok Ju 7,  Anna Philpott 8,  Benjamin D Simons 9,  Daniel E Stange 10,  Eunyoung Choi 11,  Bon-Kyoung Koo 12,  Jong Kyoung Kim 13
Affiliations

Affiliations

  • 1 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria.
  • 2 Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea; Department of New Biology, DGIST, Daegu 42988, Republic of Korea.
  • 3 Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
  • 4 Department of Surgery and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 5 Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
  • 6 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria; Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon, Gyeonggi-do, Republic of Korea.
  • 7 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
  • 8 Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
  • 9 Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Wilberforce Road, Cambridge CB3 0WA, UK.
  • 10 Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
  • 11 Department of Surgery and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: [email protected].
  • 12 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria; Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, Republic of Korea. Electronic address: [email protected].
  • 13 Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea; Department of New Biology, DGIST, Daegu 42988, Republic of Korea. Electronic address: [email protected].
PMID: 35523142 DOI: 10.1016/j.stem.2022.04.001
Abstract

Adult stem cells constantly react to local changes to ensure tissue homeostasis. In the main body of the stomach, chief cells produce digestive enzymes; however, upon injury, they undergo rapid proliferation for prompt tissue regeneration. Here, we identified p57Kip2 (p57) as a molecular switch for the reserve stem cell state of chief cells in mice. During homeostasis, p57 is constantly expressed in chief cells but rapidly diminishes after injury, followed by robust proliferation. Both single-cell RNA sequencing and dox-induced lineage tracing confirmed the sequential loss of p57 and activation of proliferation within the chief cell lineage. In corpus organoids, p57 overexpression induced a long-term reserve stem cell state, accompanied by altered niche requirements and a mature chief cell/secretory phenotype. Following the constitutive expression of p57 in vivo, chief cells showed an impaired injury response. Thus, p57 is a gatekeeper that imposes the reserve stem cell state of chief cells in homeostasis.

Keywords

Gif; Lgr5; Troy; base stem cells; gastric chief cells; p57; reserve stem cells; scRNA-seq; stem cell quiescence; stomach.

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