Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells
Han, Seungmin; Fink, Juergen; Jörg, David J.; Lee, Eunmin; Yum, Min Kyu; Chatzeli, Lemonia; Merker, Sebastian R.; Josserand, Manon; Trendafilova, Teodora; Andersson-Rolf, Amanda; Dabrowska, Catherine; Kim, Hyunki; Naumann, Ronald; Lee, Ji Hyun; Sasaki, Nobuo; Mort, Richard Lester; Basak, Onur; Clevers, Hans; Stange, Daniel E.; Philpott, Anna; Kim, Jong Kyoung; Simons, Benjamin D.; Koo, Bon Kyoung
(2019) Cell Stem Cell, volume 25, issue 3, pp. 342 - 356.e7
(Article)
Abstract
The gastric corpus epithelium is the thickest part of the gastrointestinal tract and is rapidly turned over. Several markers have been proposed for gastric corpus stem cells in both isthmus and base regions. However, the identity of isthmus stem cells (IsthSCs) and the interaction between distinct stem cell populations is
... read more
still under debate. Here, based on unbiased genetic labeling and biophysical modeling, we show that corpus glands are compartmentalized into two independent zones, with slow-cycling stem cells maintaining the base and actively cycling stem cells maintaining the pit-isthmus-neck region through a process of “punctuated” neutral drift dynamics. Independent lineage tracing based on Stmn1 and Ki67 expression confirmed that rapidly cycling IsthSCs maintain the pit-isthmus-neck region. Finally, single-cell RNA sequencing (RNA-seq) analysis is used to define the molecular identity and lineage relationship of a single, cycling, IsthSC population. These observations define the identity and functional behavior of IsthSCs.
show less
Download/Full Text
Keywords: biophysical modeling, deep tissue imaging, gastric corpus isthmus stem cell, intestine, Lgr5, punctuated neutral drift, single-cell RNA-seq, Troy, two stem cell compartments, unbiased genetic labeling, Molecular Medicine, Genetics, Cell Biology
ISSN: 1934-5909
Publisher: Cell Press
Note: Funding Information: We are grateful to Dr. John C. Marioni for help with scRNA-seq analysis, Dr. Ian James Jackson for sharing Rosa26-Fucci2a mice, Dr. Christopher J. Hindley for critical reading of the manuscript, and Sung-hwan Bae for graphic illustration. This work was supported by a number of grants, fellowships, and studentships to the following: J.F. ( Wellcome Trust ), S.H. ( HFSP LT000092/2016-L ), A.A.-R. ( Medical Research Council, UK ), H.C. ( European Research Council ), D.E.S. ( Deutsche Krebshilfe 111350 and ERC starting grant 639050 ), J.K.K. (Basic Science Research Program 2017R1C1B2007843 , 2017M3A9B6073099 , and 2017M3C7A1048448 , the National Research Foundation, S. Korea ), B.D.S. ( Wellcome Trust 098357/Z/12/Z ), and B.-K.K. ( ERC starting grant, Troy Stem Cells, 639050 ). B.D.S. also acknowledges funding from the Royal Society E.P. Abraham Research Professorship ( RP\R1\180165 ). The research team also received a core support grant from the Wellcome Trust and MRC to the WT–MRC Cambridge Stem Cell Institute. Funding Information: We are grateful to Dr. John C. Marioni for help with scRNA-seq analysis, Dr. Ian James Jackson for sharing Rosa26-Fucci2a mice, Dr. Christopher J. Hindley for critical reading of the manuscript, and Sung-hwan Bae for graphic illustration. This work was supported by a number of grants, fellowships, and studentships to the following: J.F. (Wellcome Trust), S.H. (HFSP LT000092/2016-L), A.A.-R. (Medical Research Council, UK), H.C. (European Research Council), D.E.S. (Deutsche Krebshilfe 111350 and ERC starting grant 639050), J.K.K. (Basic Science Research Program 2017R1C1B2007843, 2017M3A9B6073099, and 2017M3C7A1048448, the National Research Foundation, S. Korea), B.D.S. (Wellcome Trust 098357/Z/12/Z), and B.-K.K. (ERC starting grant, Troy Stem Cells, 639050). B.D.S. also acknowledges funding from the Royal Society E.P. Abraham Research Professorship (RP\R1\180165). The research team also received a core support grant from the Wellcome Trust and MRC to the WT?MRC Cambridge Stem Cell Institute. S.H. J.F. B.D.S. and B.-K.K. designed the experiments. S.H. J.F. M.K.Y. L.C. S.R.M. M.J. T.T. A.A.-R. C.D. H.K. R.N. J.-H.L. O.B. and B.-K.K. performed animal experiments, tissue imaging, and quantification, which were supervised by H.C. D.E.S. A.P. B.D.S. and B.-K.K. S.H. D.J.J. and B.D.S. analyzed clonal data, devised the biophysical model, and performed numerical simulation. S.H. and M.J. analyzed bulk RNA-seq data. S.H. E.L. J.K.K. B.D.S. and B.-K.K. analyzed single-cell RNA-seq data. N.S. shared the DTR-T2A-dsRed cassette. R.L.M. shared Rosa26-Fucci2a mice. O.B. and H.C. shared Ki67-CreERT2 mice. S.H. J.F. D.J.J. A.P. J.K.K. B.D.S. and B.-K.K. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: © 2019 The Authors
(Peer reviewed)
