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SCIENCE CHINA Life Sciences, Volume 61, Issue 10: 1205-1211(2018) https://doi.org/10.1007/s11427-018-9331-y

The intestinal epithelial response to damage

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  • ReceivedMar 29, 2018
  • AcceptedJun 1, 2018
  • PublishedSep 4, 2018

Abstract

The constant renewal of the intestinal epithelium is fueled by intestinal stem cells (ISCs) lying at the base of crypts, and these ISCs continuously give rise to transit-amplifying progenitor cells during homeostasis. Upon injury and loss of ISCs, the epithelium has the ability to regenerate by the dedifferentiation of progenitor cells that then regain stemness and repopulate the pool of ISCs. Epithelial cells receive cues from immune cells, mesenchymal cells and the microbiome to maintain homeostasis. This review focuses on the response of the epithelium to damage and the interplay between the different intestinal compartments.


Funded by

the California Institute for Regenerative Medicine(RN3-06525)

the Fund for Scientific Research-FNRS

Wallonie-Brussels International(WBI)

Fonds Erasme.


Acknowledgment

We thank David Castillo Azofeifa, Tomas Wald, Kara McKinley, Rachel Zwick and Adriane Joo for reviewing and editing the manuscript and help with figure designs. This work was supported by the California Institute for Regenerative Medicine (RN3-06525), Fonds De La Recherche Scientifique-FNRS, Wallonie-Brussels International (WBI) and Fonds Erasme.


Interest statement

The author(s) declare that they have no conflict of interest.


References

[1] Aoki R., Shoshkes-Carmel M., Gao N., Shin S., May C.L., Golson M.L., Zahm A.M., Ray M., Wiser C.L., Wright C.V.E., et al. Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol, 2016, 2: 175-188 CrossRef PubMed Google Scholar

[2] Aparicio-Domingo P., Romera-Hernandez M., Karrich J.J., Cornelissen F., Papazian N., Lindenbergh-Kortleve D.J., Butler J.A., Boon L., Coles M.C., Samsom J.N., et al. Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J Exp Med, 2015, 212: 1783-1791 CrossRef PubMed Google Scholar

[3] Barker N., Bartfeld S., Clevers H.. Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell, 2010, 7: 656-670 CrossRef PubMed Google Scholar

[4] Barker, N., van de Wetering, M., and Clevers, H. (2008). The intestinal stem cell. Genes Dev 22, 1856–1864. Google Scholar

[5] Barker N., van Es J.H., Kuipers J., Kujala P., van den Born M., Cozijnsen M., Haegebarth A., Korving J., Begthel H., Peters P.J., et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 2007, 449: 1003-1007 CrossRef PubMed ADS Google Scholar

[6] Barker N., van Oudenaarden A., Clevers H.. Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell, 2012, 11: 452-460 CrossRef PubMed Google Scholar

[7] Beumer J., Clevers H.. Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development, 2016, 143: 3639-3649 CrossRef PubMed Google Scholar

[8] Beyaz S., Mana M.D., Roper J., Kedrin D., Saadatpour A., Hong S.J., Bauer-Rowe K.E., Xifaras M.E., Akkad A., Arias E., et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature, 2016, 531: 53-58 CrossRef PubMed ADS Google Scholar

[9] Buczacki S.J.A., Zecchini H.I., Nicholson A.M., Russell R., Vermeulen L., Kemp R., Winton D.J.. Intestinal label-retaining cells are secretory precursors expressing lgr5. Nature, 2013, 495: 65-69 CrossRef PubMed ADS Google Scholar

[10] Costantini T.W., Bansal V., Krzyzaniak M., Putnam J.G., Peterson C.Y., Loomis W.H., Wolf P., Baird A., Eliceiri B.P., Coimbra R.. Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells. Am J Physiol Gastrointest Liver Physiol, 2010, 299: G1308-G1318 CrossRef PubMed Google Scholar

[11] Crawford P.A., Gordon J.I.. From the cover: microbial regulation of intestinal radiosensitivity. Proc Natl Acad Sci USA, 2005, 102: 13254-13259 CrossRef PubMed ADS Google Scholar

[12] Degirmenci, B., Valenta, T., Dimitrieva, S., Hausmann, G., and Basler K. (2018). GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells. Nature 558, 449–453. Google Scholar

[13] Durand A., Donahue B., Peignon G., Letourneur F., Cagnard N., Slomianny C., Perret C., Shroyer N.F., Romagnolo B.. Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proc Natl Acad Sci USA, 2012, 109: 8965-8970 CrossRef PubMed ADS Google Scholar

[14] Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.Y., Vallabhapurapu S., Scheller J., Rose-John S., Cheroutre H., Eckmann L., et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell, 2009, 15: 103-113 CrossRef PubMed Google Scholar

[15] Hanash A.M., Dudakov J.A., Hua G., O’Connor M.H., Young L.F., Singer N.V., West M.L., Jenq R.R., Holland A.M., Kappel L.W., et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity, 2012, 37: 339-350 CrossRef PubMed Google Scholar

[16] He X.C., Zhang J., Tong W.G., Tawfik O., Ross J., Scoville D.H., Tian Q., Zeng X., He X., Wiedemann L.M., et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-β-catenin signaling. Nat Genet, 2004, 36: 1117-1121 CrossRef PubMed Google Scholar

[17] Hernández-Chirlaque, C., Aranda, C.J., Ocón, B., Capitán-Cañadas, F., Ortega-González, M., Carrero, J.J., Suárez, M.D., Zarzuelo, A., de Medina, F.S. and Martínez-Augustin, O. (2016). Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis. J Crohn’s Colitis, 10, 1324–1335. Google Scholar

[18] Horiguchi H., Endo M., Kawane K., Kadomatsu T., Terada K., Morinaga J., Araki K., Miyata K., Oike Y.. ANGPTL2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis. EMBO J, 2017, 36: 409-424 CrossRef PubMed Google Scholar

[19] Igarashi M., Guarente L.. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell, 2016, 166: 436-450 CrossRef PubMed Google Scholar

[20] Ishibashi F., Shimizu H., Nakata T., Fujii S., Suzuki K., Kawamoto A., Anzai S., Kuno R., Nagata S., Ito G., et al. Contribution of ATOH1+ cells to the homeostasis, repair, and tumorigenesis of the colonic epithelium. Stem Cell Rep, 2017, 10: 27-42 CrossRef PubMed Google Scholar

[21] Itzkovitz S., Lyubimova A., Blat I.C., Maynard M., van Es J., Lees J., Jacks T., Clevers H., van Oudenaarden A.. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat Cell Biol, 2012, 14: 106-114 CrossRef PubMed Google Scholar

[22] Jadhav U., Saxena M., O’Neill N.K., Saadatpour A., Yuan G.C., Herbert Z., Murata K., Shivdasani R.A.. Dynamic reorganization of chromatin accessibility signatures during dedifferentiation of secretory precursors into Lgr5+ intestinal stem cells. Cell Stem Cell, 2017, 21: 65-77.e5 CrossRef PubMed Google Scholar

[23] Kabiri Z., Greicius G., Madan B., Biechele S., Zhong Z., Zaribafzadeh H., Edison H., Aliyev J., Wu Y., Bunte R., et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development, 2014, 141: 2206-2215 CrossRef PubMed Google Scholar

[24] Kim T.H., Escudero S., Shivdasani R.A.. Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells. Proc Natl Acad Sci USA, 2012, 109: 3932-3937 CrossRef PubMed ADS Google Scholar

[25] Lindemans C.A., Calafiore M., Mertelsmann A.M., O’Connor M.H., Dudakov J.A., Jenq R.R., Velardi E., Young L.F., Smith O.M., Lawrence G., et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature, 2015, 528: 560-564 CrossRef PubMed ADS Google Scholar

[26] Mahapatro M., Foersch S., Hefele M., He G.W., Giner-Ventura E., Mchedlidze T., Kindermann M., Vetrano S., Danese S., Günther C., et al. Programming of intestinal epithelial differentiation by IL-33 derived from pericryptal fibroblasts in response to systemic infection. Cell Rep, 2016, 15: 1743-1756 CrossRef PubMed Google Scholar

[27] McKenzie G.J., Bancroft A., Grencis R.K., McKenzie A.N.J.. A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Curr Biol, 1998, 8: 339-342 CrossRef Google Scholar

[28] Metcalfe C., Kljavin N.M., Ybarra R., de Sauvage F.J.. Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell, 2014, 14: 149-159 CrossRef PubMed Google Scholar

[29] Montgomery R.K., Carlone D.L., Richmond C.A., Farilla L., Kranendonk M.E.G., Henderson D.E., Yaa Baffour-Awuah N., Ambruzs D.M., Fogli L.K., Algra S., et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci USA, 2011, 108: 179-184 CrossRef PubMed ADS Google Scholar

[30] Muñoz J., Stange D.E., Schepers A.G., van de Wetering M., Koo B.K., Itzkovitz S., Volckmann R., Kung K.S., Koster J., Radulescu S., et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers. EMBO J, 2012, 31: 3079-3091 CrossRef PubMed Google Scholar

[31] Neurath M.F.. New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol, 2014, 7: 6-19 CrossRef PubMed Google Scholar

[32] Nusse, Y.M., Savage, A.K., Marangoni, P., Rosendahl-Huber, A.K.M., Landman, T.A., de Sauvage, F.J., Locksley, R.M., and Klein, O.D. (2018). Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559, 109–113. Google Scholar

[33] Pickert G., Neufert C., Leppkes M., Zheng Y., Wittkopf N., Warntjen M., Lehr H.A., Hirth S., Weigmann B., Wirtz S., et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med, 2009, 206: 1465-1472 CrossRef PubMed Google Scholar

[34] Pinto D., Gregorieff A., Begthel H., Clevers H.. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev, 2003, 17: 1709-1713 CrossRef PubMed Google Scholar

[35] Potten C.S., Kovacs L., Hamilton E.. Continuous labelling studies on mouse skin and intestine. Cell Prolif, 1974, 7: 271-283 CrossRef Google Scholar

[36] Powell A.E., Wang Y., Li Y., Poulin E.J., Means A.L., Washington M.K., Higginbotham J.N., Juchheim A., Prasad N., Levy S.E., et al. The pan-ErbB negative regulator lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell, 2012, 149: 146-158 CrossRef PubMed Google Scholar

[37] Quiros M., Nishio H., Neumann P.A., Siuda D., Brazil J.C., Azcutia V., Hilgarth R., O’Leary M.N., Garcia-Hernandez V., Leoni G., et al. Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J Clin Investig, 2017, 127: 3510-3520 CrossRef PubMed Google Scholar

[38] Sangiorgi E., Capecchi M.R.. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet, 2008, 40: 915-920 CrossRef PubMed Google Scholar

[39] Sato T., Clevers H.. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science, 2013, 340: 1190-1194 CrossRef PubMed ADS Google Scholar

[40] Sato T., van Es J.H., Snippert H.J., Stange D.E., Vries R.G., van den Born M., Barker N., Shroyer N.F., van de Wetering M., Clevers H.. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature, 2011, 469: 415-418 CrossRef PubMed ADS Google Scholar

[41] Sato T., Vries R.G., Snippert H.J., van de Wetering M., Barker N., Stange D.E., van Es J.H., Abo A., Kujala P., Peters P.J., et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 2009, 459: 262-265 CrossRef PubMed ADS Google Scholar

[42] Shoshkes-Carmel, M., Wang, Y.J., Wangensteen, K.J., Tóth, B., Kondo, A., Massasa, E.E., Itzkovitz, S., and Kaestner, K.H. (2018). Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. Nature 557, 242–246. Google Scholar

[43] Spits H., Artis D., Colonna M., Diefenbach A., Di Santo J.P., Eberl G., Koyasu S., Locksley R.M., McKenzie A.N.J., Mebius R.E., et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol, 2013, 13: 145-149 CrossRef PubMed Google Scholar

[44] Stzepourginski I., Nigro G., Jacob J.M., Dulauroy S., Sansonetti P.J., Eberl G., Peduto L.. CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury. Proc Natl Acad Sci USA, 2017, 114: E506-E513 CrossRef PubMed Google Scholar

[45] Takeda N., Jain R., LeBoeuf M.R., Wang Q., Lu M.M., Epstein J.A.. Interconversion between intestinal stem cell populations in distinct niches. Science, 2011, 334: 1420-1424 CrossRef PubMed ADS Google Scholar

[46] Taniguchi K., Wu L.W., Grivennikov S.I., de Jong P.R., Lian I., Yu F.X., Wang K., Ho S.B., Boland B.S., Chang J.T., et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature, 2015, 519: 57-62 CrossRef PubMed ADS Google Scholar

[47] Tetteh P.W., Basak O., Farin H.F., Wiebrands K., Kretzschmar K., Begthel H., van den Born M., Korving J., de Sauvage F., van Es J.H., et al. Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell, 2016, 18: 203-213 CrossRef PubMed Google Scholar

[48] Tian H., Biehs B., Chiu C., Siebel C.W., Wu Y., Costa M., de Sauvage F.J., Klein O.D.. Opposing activities of notch and wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep, 2015, 11: 33-42 CrossRef PubMed Google Scholar

[49] Tian H., Biehs B., Warming S., Leong K.G., Rangell L., Klein O.D., de Sauvage F.J.. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature, 2011, 478: 255-259 CrossRef PubMed ADS Google Scholar

[50] Tsuchiya T., Fukuda S., Hamada H., Nakamura A., Kohama Y., Ishikawa H., Tsujikawa K., Yamamoto H.. Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol, 2003, 171: 5507-5513 CrossRef Google Scholar

[51] van der Flier L.G., Haegebarth A., Stange D.E., van de Wetering M., Clevers H.. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology, 2009, 137: 15-17 CrossRef PubMed Google Scholar

[52] van der Flier L.G., van Gijn M.E., Hatzis P., Kujala P., Haegebarth A., Stange D.E., Begthel H., van den Born M., Guryev V., Oving I., et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell, 2009, 136: 903-912 CrossRef PubMed Google Scholar

[53] van Es J.H., Sato T., van de Wetering M., Lyubimova A., Yee Nee A.N., Gregorieff A., Sasaki N., Zeinstra L., van den Born M., Korving J., et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol, 2012, 14: 1099-1104 CrossRef PubMed Google Scholar

[54] Van Landeghem L., Chevalier J., Mahé M.M., Wedel T., Urvil P., Derkinderen P., Savidge T., Neunlist M.. Enteric glia promote intestinal mucosal healing via activation of focal adhesion kinase and release of proEGF. Am J Physiol Gastrointest Liver Physiol, 2011, 300: G976-G987 CrossRef PubMed Google Scholar

[55] von Moltke J., Ji M., Liang H.E., Locksley R.M.. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature, 2016, 529: 221-225 CrossRef PubMed ADS Google Scholar

[56] Wu H., Tremaroli V., Bäckhed F.. Linking microbiota to human diseases: a systems biology perspective. Trends Endocrinol Metab, 2015, 26: 758-770 CrossRef PubMed Google Scholar

[57] Yan K.S., Gevaert O., Zheng G.X.Y., Anchang B., Probert C.S., Larkin K.A., Davies P.S., Cheng Z.F., Kaddis J.S., Han A., et al. Intestinal enteroendocrine lineage cells possess homeostatic and injury-inducible stem cell activity. Cell Stem Cell, 2017, 21: 78-90.e6 CrossRef PubMed Google Scholar

[58] Yilmaz Ö.H., Katajisto P., Lamming D.W., Gültekin Y., Bauer-Rowe K.E., Sengupta S., Birsoy K., Dursun A., Yilmaz V.O., Selig M., et al. MTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature, 2012, 486: 490-495 CrossRef PubMed ADS Google Scholar

[59] Yui, S., Azzolin, L., Maimets, M., Pedersen, M.T., Fordham, R.P., Hansen, S.L., Larsen, H.L., Guiu, J., Alves, M.R.P., Rundsten, C.F., et al. (2018). YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell 22, 35–49.e7. Google Scholar

[60] Zou W.Y., Blutt S.E., Zeng X.L., Chen M.S., Lo Y.H., Castillo-Azofeifa D., Klein O.D., Shroyer N.F., Donowitz M., Estes M.K.. Epithelial WNT ligands are essential drivers of intestinal stem cell activation. Cell Rep, 2018, 22: 1003-1015 CrossRef PubMed Google Scholar

  • Figure 1

    Stem cell-fueled renewal of the intestinal epithelium. The intestinal epithelium is composed of two compartments, namely crypts and villi. The crypts harbor ISCs intermingled between Paneth cells at their base. ISCs divide each day to give rise to secretory and absorptive progenitor cells, also known as TA cells. While moving up along the crypt-villus axis, the TA differentiate into the various epithelial cells composing the villi. Homeostasis of the intestinal epithelium is maintained through the interplay between epithelial cells, immune cells, cytokine signaling and the microbiota.

  • Figure 2

    Stem cell ablation and lineage tracing point to plasticity in the intestinal epithelium. Cre-mediated recombination in progenitor cells (secretory or absorptive) is indicated by gradient blue in the labeled cells. After ablation of Lgr5+ cells, progenitor cells dedifferentiate and replenish the pool of stem cells. These cells give rise to all types of differentiated epithelial cells, as indicated by the ribbon of labeled cells going up the crypt-villus axis.

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