P57 Imposes the Reserve Stem Cell State of Gastric Chief Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2022 May 6

PMID 35523142

Authors

Ji-Hyun Lee

Somi Kim

Seungmin Han

Jimin Min

Brianna Caldwell

Aileen-Diane Bamford

Andreia Sofia Batista Rocha

Jinyoung Park

Sieun Lee

Szu-Hsien Sam Wu

Heetak Lee

Juergen Fink

Sandra Pilat-Carotta

Jihoon Kim

Manon Josserand

Reka Szep-Bakonyi

Yohan An

Young Seok Ju

Anna Philpott

Benjamin D Simons

Daniel E Stange

Eunyoung Choi

Bon-Kyoung Koo

Jong Kyoung Kim

Affiliations

Soon will be listed here.

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 p57 (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.

Citing Articles

Helicobacter pylori, microbiota and gastric cancer - principles of microorganism-driven carcinogenesis.

Wizenty J, Sigal M Nat Rev Gastroenterol Hepatol. 2025; .

PMID: 40011753 DOI: 10.1038/s41575-025-01042-2.

Emerging role of spasmolytic polypeptide-expressing metaplasia in gastric cancer.

Ye Q, Zhu Y, Ma Y, Wang Z, Xu G J Gastrointest Oncol. 2025; 15(6):2673-2683.

PMID: 39816029 PMC: 11732338. DOI: 10.21037/jgo-24-508.

Origins of cancer: ain't it just mature cells misbehaving?.

Cho C, Brown J, Mills J EMBO J. 2024; 43(13):2530-2551.

PMID: 38773319 PMC: 11217308. DOI: 10.1038/s44318-024-00099-0.

Cellular plasticity and fate determination in gastric carcinogenesis.

He Z, Hu X, He T, Zhao T iScience. 2024; 27(4):109465.

PMID: 38550991 PMC: 10973593. DOI: 10.1016/j.isci.2024.109465.

Amphiregulin Switches Progenitor Cell Fate for Lineage Commitment During Gastric Mucosal Regeneration.

Lee S, Won Y, Gibbs D, Caldwell B, Goldstein A, Choi E Gastroenterology. 2024; 167(3):469-484.

PMID: 38492892 PMC: 11260537. DOI: 10.1053/j.gastro.2024.03.009.

References

Leushacke M, Tan S, Wong A, Swathi Y, Hajamohideen A, Tan L . Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol. 2017; 19(7):774-786. DOI: 10.1038/ncb3541. View

Bergen V, Lange M, Peidli S, Wolf F, Theis F . Generalizing RNA velocity to transient cell states through dynamical modeling. Nat Biotechnol. 2020; 38(12):1408-1414. DOI: 10.1038/s41587-020-0591-3. View

van Es J, Sato T, van de Wetering M, Lyubimova A, Yee Nee A, Gregorieff A . Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol. 2012; 14(10):1099-1104. PMC: 3789123. DOI: 10.1038/ncb2581. View

Seidlitz T, Chen Y, Uhlemann H, Scholch S, Kochall S, Merker S . Mouse Models of Human Gastric Cancer Subtypes With Stomach-Specific CreERT2-Mediated Pathway Alterations. Gastroenterology. 2019; 157(6):1599-1614.e2. PMC: 6902245. DOI: 10.1053/j.gastro.2019.09.026. View

Furutachi S, Matsumoto A, Nakayama K, Gotoh Y . p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis. EMBO J. 2013; 32(7):970-81. PMC: 3616292. DOI: 10.1038/emboj.2013.50. View

Mootha V, Lindgren C, Eriksson K, Subramanian A, Sihag S, Lehar J . PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003; 34(3):267-73. DOI: 10.1038/ng1180. View

Lun A, McCarthy D, Marioni J . A step-by-step workflow for low-level analysis of single-cell RNA-seq data with Bioconductor. F1000Res. 2016; 5:2122. PMC: 5112579. DOI: 10.12688/f1000research.9501.2. View

Arnold K, Sarkar A, Yram M, Polo J, Bronson R, Sengupta S . Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell. 2011; 9(4):317-29. PMC: 3538360. DOI: 10.1016/j.stem.2011.09.001. View

He G, Siddik Z, Huang Z, Wang R, Koomen J, Kobayashi R . Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene. 2005; 24(18):2929-43. DOI: 10.1038/sj.onc.1208474. View

10.

Han S, Fink J, Jorg D, Lee E, Yum M, Chatzeli L . Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells. Cell Stem Cell. 2019; 25(3):342-356.e7. PMC: 6739486. DOI: 10.1016/j.stem.2019.07.008. View

11.

Burclaff J, Willet S, Saenz J, Mills J . Proliferation and Differentiation of Gastric Mucous Neck and Chief Cells During Homeostasis and Injury-induced Metaplasia. Gastroenterology. 2019; 158(3):598-609.e5. PMC: 7010566. DOI: 10.1053/j.gastro.2019.09.037. View

12.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

13.

Busslinger G, Weusten B, Bogte A, Begthel H, Brosens L, Clevers H . Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution. Cell Rep. 2021; 34(10):108819. DOI: 10.1016/j.celrep.2021.108819. View

14.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

15.

Hata M, Kinoshita H, Hayakawa Y, Konishi M, Tsuboi M, Oya Y . GPR30-Expressing Gastric Chief Cells Do Not Dedifferentiate But Are Eliminated via PDK-Dependent Cell Competition During Development of Metaplasia. Gastroenterology. 2020; 158(6):1650-1666.e15. PMC: 8796250. DOI: 10.1053/j.gastro.2020.01.046. View

16.

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

17.

Ganger M, Dietz G, Ewing S . A common base method for analysis of qPCR data and the application of simple blocking in qPCR experiments. BMC Bioinformatics. 2017; 18(1):534. PMC: 5709943. DOI: 10.1186/s12859-017-1949-5. View

18.

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

19.

Setty M, Kiseliovas V, Levine J, Gayoso A, Mazutis L, Peer D . Characterization of cell fate probabilities in single-cell data with Palantir. Nat Biotechnol. 2019; 37(4):451-460. PMC: 7549125. DOI: 10.1038/s41587-019-0068-4. View

20.

Ayyaz A, Kumar S, Sangiorgi B, Ghoshal B, Gosio J, Ouladan S . Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature. 2019; 569(7754):121-125. DOI: 10.1038/s41586-019-1154-y. View