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Science China Life Sciences

, Volume 61, Issue 10, pp 1205–1211 | Cite as

The intestinal epithelial response to damage

  • Laura Weichselbaum
  • Ophir D. Klein
Review

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.

Keywords

intestine regeneration microenvironment 

Notes

Acknowledgements

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.

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. (2016). Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol 2, 175–188.CrossRefPubMedGoogle 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. (2015). Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J Exp Med 212, 1783–1791.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Barker, N., Bartfeld, S., and Clevers, H. (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell 7, 656–670.CrossRefPubMedGoogle Scholar
  4. Barker, N., van de Wetering, M., and Clevers, H. (2008). The intestinal stem cell. Genes Dev 22, 1856–1864.CrossRefPubMedPubMedCentralGoogle 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. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007.CrossRefPubMedGoogle Scholar
  6. Barker, N., van Oudenaarden, A., and Clevers, H. (2012). Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell 11, 452–460.CrossRefPubMedGoogle Scholar
  7. Beumer, J., and Clevers, H. (2016). Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development 143, 3639–3649.CrossRefPubMedGoogle 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. (2016). High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Buczacki, S.J.A., Zecchini, H.I., Nicholson, A.M., Russell, R., Vermeulen, L., Kemp, R., and Winton, D.J. (2013). Intestinal label-retaining cells are secretory precursors expressing lgr5. Nature 495, 65–69.CrossRefPubMedGoogle 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., and Coimbra, R. (2010). Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells. Am J Physiol Gastrointest Liver Physiol 299, G1308–G1318.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Crawford, P.A., and Gordon, J.I. (2005). From the cover: microbial regulation of intestinal radiosensitivity. Proc Natl Acad Sci USA 102, 13254–13259.CrossRefPubMedGoogle Scholar
  12. Degirmenci, B., Valenta, T., Dimitrieva, S., Hausmann, G., and Basler K. (2018). GLI1-expressing mesenchymal cells form the essential Wntsecreting niche for colon stem cells. Nature 558, 449–453.CrossRefPubMedGoogle Scholar
  13. Durand, A., Donahue, B., Peignon, G., Letourneur, F., Cagnard, N., Slomianny, C., Perret, C., Shroyer, N.F., and Romagnolo, B. (2012). Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proc Natl Acad Sci USA 109, 8965–8970.CrossRefPubMedGoogle 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. (2009). IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113.CrossRefPubMedPubMedCentralGoogle 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. (2012). Interleukin-22 protects intestinal stem cells from immunemediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37, 339–350.CrossRefPubMedPubMedCentralGoogle 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. (2004). BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-β-catenin signaling. Nat Genet 36, 1117–1121.CrossRefPubMedGoogle 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 antibiotictreated mice are highly susceptible to epithelial injury in DSS colitis. J Crohn’s Colitis, 10, 1324–1335.CrossRefGoogle Scholar
  18. Horiguchi, H., Endo, M., Kawane, K., Kadomatsu, T., Terada, K., Morinaga, J., Araki, K., Miyata, K., and Oike, Y. (2017). ANGPTL2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis. EMBO J 36, 409–424.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Igarashi, M., and Guarente, L. (2016). mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell 166, 436–450.CrossRefPubMedGoogle Scholar
  20. Ishibashi, F., Shimizu, H., Nakata, T., Fujii, S., Suzuki, K., Kawamoto, A., Anzai, S., Kuno, R., Nagata, S., Ito, G., et al. (2017). Contribution of ATOH1+ cells to the homeostasis, repair, and tumorigenesis of the colonic epithelium. Stem Cell Rep 10, 27–42.CrossRefGoogle Scholar
  21. Itzkovitz, S., Lyubimova, A., Blat, I.C., Maynard, M., van Es, J., Lees, J., Jacks, T., Clevers, H., and van Oudenaarden, A. (2012). Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat Cell Biol 14, 106–114.CrossRefGoogle Scholar
  22. Jadhav, U., Saxena, M., O’Neill, N.K., Saadatpour, A., Yuan, G.C., Herbert, Z., Murata, K., and Shivdasani, R.A. (2017). Dynamic reorganization of chromatin accessibility signatures during dedifferentiation of secretory precursors into Lgr5+ intestinal stem cells. Cell Stem Cell 21, 65–77.e5.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kabiri, Z., Greicius, G., Madan, B., Biechele, S., Zhong, Z., Zaribafzadeh, H., Edison, H., Aliyev, J., Wu, Y., Bunte, R., et al. (2014). Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 141, 2206–2215.CrossRefPubMedGoogle Scholar
  24. Kim, T.H., Escudero, S., and Shivdasani, R.A. (2012). Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells. Proc Natl Acad Sci USA 109, 3932–3937.CrossRefPubMedGoogle 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. (2015). Interleukin-22 promotes intestinal-stem-cellmediated epithelial regeneration. Nature 528, 560–564.CrossRefPubMedPubMedCentralGoogle 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. (2016). Programming of intestinal epithelial differentiation by IL-33 derived from pericryptal fibroblasts in response to systemic infection. Cell Rep 15, 1743–1756.CrossRefPubMedGoogle Scholar
  27. McKenzie, G.J., Bancroft, A., Grencis, R.K., and McKenzie, A.N.J. (1998). A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Curr Biol 8, 339–342.CrossRefPubMedGoogle Scholar
  28. Metcalfe, C., Kljavin, N.M., Ybarra, R., and de Sauvage, F.J. (2014). Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14, 149–159.CrossRefPubMedGoogle 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. (2011). Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci USA 108, 179–184.CrossRefPubMedGoogle 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. (2012). The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers. EMBO J 31, 3079–3091.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Neurath, M.F. (2014). New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol 7, 6–19.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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. (2009). STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206, 1465–1472.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Pinto, D., Gregorieff, A., Begthel, H., and Clevers, H. (2003). Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17, 1709–1713.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Potten, C.S., Kovacs, L., and Hamilton, E. (1974). Continuous labelling studies on mouse skin and intestine. Cell Prolif 7, 271–283.CrossRefGoogle 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. (2012). The pan-ErbB negative regulator lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149, 146–158.CrossRefPubMedPubMedCentralGoogle 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. (2017). Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J Clin Investig 127, 3510–3520.CrossRefPubMedGoogle Scholar
  38. Sangiorgi, E., and Capecchi, M.R. (2008). Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40, 915–920.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Sato, T., and Clevers, H. (2013). Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194.CrossRefPubMedGoogle 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., and Clevers, H. (2011). Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418.CrossRefPubMedGoogle 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. (2009). Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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. (2013). Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol 13, 145–149.CrossRefPubMedGoogle Scholar
  44. Stzepourginski, I., Nigro, G., Jacob, J.M., Dulauroy, S., Sansonetti, P.J., Eberl, G., and Peduto, L. (2017). CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury. Proc Natl Acad Sci USA 114, E506–E513.CrossRefPubMedGoogle Scholar
  45. Takeda, N., Jain, R., LeBoeuf, M.R., Wang, Q., Lu, M.M., and Epstein, J.A. (2011). Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424.CrossRefPubMedPubMedCentralGoogle 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. (2015). A gp130- Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62.CrossRefPubMedPubMedCentralGoogle 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. (2016). Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell 18, 203–213.CrossRefPubMedGoogle Scholar
  48. Tian, H., Biehs, B., Chiu, C., Siebel, C.W., Wu, Y., Costa, M., de Sauvage, F.J., and Klein, O.D. (2015). Opposing activities of notch and wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep 11, 33–42.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Tian, H., Biehs, B., Warming, S., Leong, K.G., Rangell, L., Klein, O.D., and de Sauvage, F.J. (2011). A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Tsuchiya, T., Fukuda, S., Hamada, H., Nakamura, A., Kohama, Y., Ishikawa, H., Tsujikawa, K., and Yamamoto, H. (2003). Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol 171, 5507–5513.CrossRefPubMedGoogle Scholar
  51. van der Flier, L.G., Haegebarth, A., Stange, D.E., van de Wetering, M., and Clevers, H. (2009). OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17.CrossRefPubMedGoogle 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. (2009). Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912.CrossRefPubMedGoogle 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. (2012). Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14, 1099–1104.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Van Landeghem, L., Chevalier, J., Mahé, M.M., Wedel, T., Urvil, P., Derkinderen, P., Savidge, T., and Neunlist, M. (2011). Enteric glia promote intestinal mucosal healing via activation of focal adhesion kinase and release of proEGF. Am J Physiol Gastrointest Liver Physiol 300, G976–G987.CrossRefPubMedPubMedCentralGoogle Scholar
  55. von Moltke, J., Ji, M., Liang, H.E., and Locksley, R.M. (2016). Tuft-cellderived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225.CrossRefPubMedGoogle Scholar
  56. Wu, H., Tremaroli, V., and Bäckhed, F. (2015). Linking microbiota to human diseases: a systems biology perspective. Trends Endocrinol Metab 26, 758–770.CrossRefPubMedGoogle 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. (2017). Intestinal enteroendocrine lineage cells possess homeostatic and injuryinducible stem cell activity. Cell Stem Cell 21, 78–90.e6.CrossRefPubMedPubMedCentralGoogle 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. (2012). MTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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., and Estes, M.K. (2018). Epithelial WNT ligands are essential drivers of intestinal stem cell activation. Cell Rep 22, 1003–1015.CrossRefPubMedPubMedCentralGoogle Scholar

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© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Program in Craniofacial Biology and Department of Orofacial SciencesUniversity of CaliforniaSan FranciscoUSA
  2. 2.Institute for Medical ImmunologyUniversité Libre de BruxellesGosseliesBelgium
  3. 3.Laboratory of Experimental GastroenterologyUniversité libre de BruxellesBrusselsBelgium
  4. 4.Department of Pediatrics and Institute for Human GeneticsUniversity of CaliforniaSan FranciscoUSA

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