Cell fate specification and differentiation in the adult mammalian intestine

Abstract

Intestinal stem cells at the bottom of crypts fuel the rapid renewal of the different cell types that constitute a multitasking tissue. The intestinal epithelium facilitates selective uptake of nutrients while acting as a barrier for hostile luminal contents. Recent discoveries have revealed that the lineage plasticity of committed cells — combined with redundant sources of niche signals — enables the epithelium to efficiently repair tissue damage. New approaches such as single-cell transcriptomics and the use of organoid models have led to the identification of the signals that guide fate specification of stem cell progeny into the six intestinal cell lineages. These cell types display context-dependent functionality and can adapt to different requirements over their lifetime, as dictated by their microenvironment. These new insights into stem cell regulation and fate specification could aid the development of therapies that exploit the regenerative capacity and functionality of the gut.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Intestinal stem cells and their regulatory signals.
Fig. 2: Lineage specification in the intestinal epithelium.
Fig. 3: Dynamics in intestinal cell function along the crypt–villus axis.

References

  1. 1.

    Hounnou, G., Destrieux, C., Desmé, J., Bertrand, P. & Velut, S. Anatomical study of the length of the human intestine. Surg. Radiol. Anat. 24, 290–294 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Kiela, P. R. & Ghishan, F. K. Physiology of intestinal absorption and secretion. Best Pract. Res. 30, 145–159 (2016).

    CAS  Article  Google Scholar 

  3. 3.

    Snoeck, V., Goddeeris, B. & Cox, E. The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes Infect. 7, 997–1004 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017). Haber et al. provide the first in-depth description of all small-intestinal cell types using single-cell RNA sequencing.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Bjerknes, M. & Cheng, H. The stem-cell zone of the small intestinal epithelium. III. Evidence from columnar, enteroendocrine, and mucous cells in the adult mouse. Am. J. Anat. 160, 77–91 (1981).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Basak, O. et al. Mapping early fate determination in Lgr5+ crypt stem cells using a novel Ki67-RFP allele. EMBO J. 33, 1–12 (2014).

    Article  CAS  Google Scholar 

  7. 7.

    Cheng, H. & Leblond, C. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am. J. Anat. 141, 537–561 (1974).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Bjerknes, M. & Cheng, H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 116, 7–14 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Winton, D. J., Blount, M. A. & Ponder, B. A. A clonal marker induced by mutation in mouse intestinal epithelium. Nature 333, 463–466 (1988).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007). In this study, Barker et al. identify Lgr5 as a target gene of the WNT signalling pathway that marks the adult stem cells of the small intestine and colon using lineage tracing.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Gerbe, F. et al. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J. Cell Biol. 192, 767–780 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    de Lau, W. et al. Peyer’s Patch M cells derived from Lgr5+ stem cells require SpiB and are induced by RankL in cultured ‘miniguts’. Mol. Cell. Biol. 32, 3639–3647 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009). Sato et al. describe the first intestinal organoid culture.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Schepers, A. G., Vries, R., van den Born, M., van de Wetering, M. & Clevers, H. Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J. 30, 1104–1109 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Ponder, B. A. et al. Derivation of mouse intestinal crypts from single progenitor cells. Nature 313, 689–691 (1985).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Griffiths, D. F., Davies, S. J., Williams, D., Williams, G. T. & Williams, E. D. Demonstration of somatic mutation and colonic crypt clonality by X-linked enzyme histochemistry. Nature 333, 461–463 (1988).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Ritsma, L. et al. Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging. Nature 507, 362–365 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Muñoz, J. et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers. EMBO J. 31, 3079–3091 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Kim, T. H. et al. Single-cell transcript profiles reveal multilineage priming in early progenitors derived from Lgr5+ intestinal stem cells. Cell Rep. 16, 2053–2060 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Garabedian, E. M., Roberts, L. J., McNevin, M. S. & Gordon, J. I. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J. Biol. Chem. 272, 23729–23740 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    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 109, 3932–3937 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Durand, A. et al. 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 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Mori-Akiyama, Y. et al. SOX9 is required for the differentiation of Paneth cells in the intestinal epithelium. Gastroenterology 133, 539–546 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Bastide, P. et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J. Cell Biol. 178, 635–648 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Shroyer, N. F., Wallis, D., Venken, K. J. T., Bellen, H. J. & Zoghbi, H. Y. Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev. 19, 2412–2417 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Blache, P. et al. SOX9 is an intestine crypt transcription factor, the CDX2 and MUC2 genes. J. Cell Biol. 166, 37–47 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    VanDussen, K. L. et al. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139, 488–497 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Shroyer, N. F. et al. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132, 2478–2488 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    van Es, J. H., de Geest, N., van de Born, M., Clevers, H. & Hassan, B. A. Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. Nat. Commun. 1, 18 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  34. 34.

    van Es, J. H. et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  35. 35.

    van Es, J. H. et al. Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion. Proc. Natl Acad. Sci. USA 116, 26599–26605 (2019).

    Article  CAS  Google Scholar 

  36. 36.

    Boisset, J. C. et al. Mapping the physical network of cellular interactions. Nat. Methods 15, 547–553 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Sasaki, N. et al. Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. Proc. Natl Acad. Sci. USA 113, E5399–E5407 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Kondo, A. & Kaestner, K. H. Emerging diverse roles of telocytes. Development 146, dev175018 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    San Roman, A. K., Jayewickreme, C. D., Murtaugh, L. C. & Shivdasani, R. A. Wnt secretion from epithelial cells and subepithelial myofibroblasts is not required in the mouse intestinal stem cell niche in vivo. Stem Cell Reports 2, 127–134 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Farin, H. F., Van Es, J. H. & Clevers, H. Redundant sources of Wnt regulate intestinal stem cells and promote formation of paneth cells. Gastroenterology 143, 1518–1529 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Aoki, R. et al. Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol. Gastroenterol. Hepatol. 2, 175–188 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Shoshkes-Carmel, M. et al. Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. Nature 557, 242–246 (2018). Shoshkes-Carmel et al. describe the role of WNT molecules derived from the stroma to support intestinal stem cells using different mouse models.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Stzepourginski, I. et al. 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 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Greicius, G. et al. PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo. Proc. Natl Acad. Sci. USA 115, E3173–E3181 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Yan, K. S. et al. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 545, 238–242 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    van Landeghem, L. et al. 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 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Bar-Ephraim, Y. E., Kretzschmar, K. & Clevers, H. Organoids in immunological research. Nat. Rev. Immunol. 20, 279–293 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Beumer, J. & Clevers, H. Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development 143, 3639–3649 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Potten, C. S., Hume, W. J., Reid, P. & Cairns, J. The segregation of DNA in epithelial stem cells. Cell 15, 899–906 (1978).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Escobar, M. et al. Intestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation. Nat. Commun. 2, 258 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 482, 120–120 (2012).

    CAS  Article  Google Scholar 

  55. 55.

    Yan, K. S. et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc. Natl Acad. Sci. USA 109, 466–471 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011). Takeda et al. find that CBCs and +4 cells can directly interconvert.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Montgomery, R. K. et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc. Natl Acad. Sci. USA 108, 179–184 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Breault, D. T. et al. Generation of mTert-GFP mice as a model to identify and study tissue progenitor cells. Proc. Natl Acad. Sci. USA 105, 10420–10425 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Powell, A. E. et al. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149, 146–158 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Itzkovitz, S. et al. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat. Cell Biol. 14, 106–114 (2012).

    CAS  Article  Google Scholar 

  61. 61.

    Wong, V. W. Y. et al. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat. Cell Biol. 14, 401–408 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Yan, K. S. et al. Intestinal enteroendocrine lineage cells possess homeostatic and injury-inducible stem cell activity. Cell Stem Cell 21, 78–90.e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Buczacki, S. J. A. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 65–69 (2013). Buczacki et al. resolve the identity and fate of label-retaining cells in the intestine using lineage tracing.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Dekaney, C. M., Gulati, A. S., Garrison, A. P., Helmrath, M. A. & Henning, S. J. Regeneration of intestinal stem/progenitor cells following doxorubicin treatment of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G461–G470 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Metcalfe, C., Kljavin, N. M., Ybarra, R. & De Sauvage, F. J. Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14, 149–159 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Jadhav, U. et al. Dynamic reorganization of chromatin accessibility signatures during dedifferentiation of secretory precursors into Lgr5+ intestinal stem cells. Cell Stem Cell 21, 65–77.e5 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat. Cell Biol. 14, 1099–1104 (2012). The work by van Es et al. provides evidence, using lineage tracing, indicating that cells committed to the secretory lineage can revert to a stem cell state when damage occurs.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Tetteh, P. W. et al. Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell 18, 203–213 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Roche, K. C. et al. SOX9 maintains reserve stem cells and preserves radioresistance in mouse small intestine. Gastroenterology 149, 1553–1563 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Castillo-Azofeifa, D. et al. Atoh1+ secretory progenitors possess renewal capacity independent of Lgr5+ cells during colonic regeneration. EMBO J. 38, e99984 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Schmitt, M. et al. Paneth cells respond to inflammation and contribute to tissue regeneration by acquiring stem-like features through SCF/c-Kit signaling. Cell Rep. 24, 2312–2328.e7 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Yu, S. et al. Paneth cell multipotency induced by Notch activation following injury. Cell Stem Cell 23, 46–59.e5 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Harnack, C. et al. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat. Commun. 10, 4368 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Kim, T.-H. et al. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506, 511–515 (2014). Kin et al. describe the chromatin landscape of intestinal crypt cells, revealing permissive chromatin that could explain lineage plasticity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Kaaij, L. T. et al. DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus. Genome Biol. 14, R50 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Forn, M. et al. Overlapping DNA methylation dynamics in mouse intestinal cell differentiation and early stages of malignant progression. PLoS ONE 10, e0123263 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Suelves, M., Carrió, E., Núñez-Álvarez, Y. & Peinado, M. A. DNA methylation dynamics in cellular commitment and differentiation. Brief. Funct. Genomics 15, 443–453 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Guiu, J. et al. Tracing the origin of adult intestinal stem cells. Nature 570, 107–111 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Kim, K.-A. et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science 309, 1256–1259 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Romesser, P. B. et al. Preclinical murine platform to evaluate therapeutic countermeasures against radiation-induced gastrointestinal syndrome. Proc. Natl Acad. Sci. USA 116, 20672–20678 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    Ashton, G. H. et al. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Dev. Cell 19, 259–269 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Gregorieff, A. & Wrana, J. L. Hippo signalling in intestinal regeneration and cancer. Curr. Opin. Cell Biol. 48, 17–25 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Moya, I. M. & Halder, G. Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat. Rev. Mol. Cell Biol. 20, 211–226 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Barry, E. R. et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106–110 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  85. 85.

    Cai, J. et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Gregorieff, A., Liu, Y., Inanlou, M. R., Khomchuk, Y. & Wrana, J. L. Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer. Nature 526, 715–718 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Karpowicz, P., Perez, J. & Perrimon, N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135–4145 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Yui, S. et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell 22, 35–49.e7 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Romera-Hernández, M. et al. Yap1-driven intestinal repair is controlled by group 3 innate lymphoid cells. Cell Rep. 30, 37–45.e3 (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  90. 90.

    Taniguchi, K. et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Azzolin, L. et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Serra, D. et al. Self-organization and symmetry breaking in intestinal organoid development. Nature 569, 66–72 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Nusse, Y. M. et al. Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559, 109–113 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Ayyaz, A. et al. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature 569, 121–125 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Jenne, D. E. & Tschopp, J. Clusterin: the intriguing guises of a widely expressed glycoprotein. Trends Biochem. Sci. 17, 154–159 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Ammar, H. & Closset, J. L. Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway. J. Biol. Chem. 283, 12851–12861 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Heath, J. P. Epithelial cell migration in the intestine. Cell Biol. Int. 20, 139–146 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98.

    Krndija, D. et al. Active cell migration is critical for steady-state epithelial turnover in the gut. Science 365, 705–710 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Merlos-Suárez, A. et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8, 511–524 (2011).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  100. 100.

    Batlle, E. et al. β-Catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111, 251–263 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Klein, R. Eph/ephrin signalling during development. Development 139, 4105–4109 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Van de Wetering, M. et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Fre, S. et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964–968 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. 104.

    van Es, J. H. et al. Dll1 marks early secretory progenitors in gut crypts that can revert to stem cells upon tissue damage. Nat. Cell Biol. 14, 1099–1104 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    Jensen, J. et al. Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, 36–44 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Suzuki, K. et al. Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine. Biochem. Biophys. Res. Commun. 328, 348–352 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Pellegrinet, L. et al. Dll1- and Dll4-mediated Notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140, 1230–1240.e7 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Yang, Q., Bermingham, N. A., Finegold, M. J. & Zoghbi, H. Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155–2158 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Riccio, O. et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 9, 377–383 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Roth, S. et al. Paneth cells in intestinal homeostasis and tissue injury. PLoS ONE 7, e38965 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Basak, O. et al. Induced quiescence of Lgr5+ stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell 20, 177–190.e4 (2017).

    CAS  Article  Google Scholar 

  112. 112.

    Alexandre, C., Baena-Lopez, A. & Vincent, J.-P. Patterning and growth control by membrane-tethered Wingless. Nature 505, 180–185 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Farin, H. F. et al. Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature 530, 340–343 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Fevr, T., Robine, S., Louvard, D. & Huelsken, J. Wnt/β-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol. Cell. Biol. 27, 7551–7559 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Sansom, O. J. et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 18, 1385–1390 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Kim, H.-T. et al. WNT/RYK signaling restricts goblet cell differentiation during lung development and repair. Proc. Natl Acad. Sci. USA 116, 25697–25706 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Yin, X. et al. Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny. Nat. Methods 11, 106–112 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Heuberger, J. et al. Shp2/MAPK signaling controls goblet/Paneth cell fate decisions in the intestine. Proc. Natl Acad. Sci. USA 111, 3472–3477 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Ghaleb, A. M., Aggarwal, G., Bialkowska, A. B., Nandan, M. O. & Yang, V. W. Notch inhibits expression of the Krüppel-like factor 4 tumor suppressor in the intestinal epithelium. Mol. Cancer Res. 6, 1920–1927 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Katz, J. P. et al. The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development 129, 2619–2628 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Noah, T. K., Kazanjian, A., Whitsett, J. & Shroyer, N. F. SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells. Exp. Cell Res. 316, 452–465 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Gregorieff, A. et al. The Ets-domain transcription factor spdef promotes maturation of goblet and Paneth cells in the intestinal epithelium. Gastroenterology 137, 1333–1345.e3 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  123. 123.

    Schonhoff, S. E., Giel-Moloney, M. & Leiter, A. B. Minireview: development and differentiation of gut endocrine cells. Endocrinology 145, 2639–2644 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

    Lee, J. C. et al. Regulation of the pancreatic pro-endocrine gene neurogenin3. Diabetes 50, 928–936 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Jenny, M. et al. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J. 21, 6338–6347 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    López-Díaz, L. et al. Intestinal neurogenin 3 directs differentiation of a bipotential secretory progenitor to endocrine cell rather than goblet cell fate. Dev. Biol. 309, 298–305 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Bjerknes, M. & Cheng, H. Cell lineage metastability in Gfi1-deficient mouse intestinal epithelium. Dev. Biol. 345, 49–63 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Wang, Y., Giel-Moloney, M., Rindi, G. & Leiter, A. B. Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active β-catenin. Proc. Natl Acad. Sci. USA 104, 11328–11333 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129.

    Krentz, N. A. J. et al. Phosphorylation of NEUROG3 links endocrine differentiation to the cell cycle in pancreatic progenitors. Dev. Cell 41, 129–142.e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Azzarelli, R. et al. Multi-site neurogenin3 phosphorylation controls pancreatic endocrine differentiation. Dev. Cell 41, 274–286.e5 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    He, L., Si, G., Huang, J., Samuel, A. D. T. & Perrimon, N. Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. Nature 555, 103–106 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Schneider, C., O’Leary, C. E. & Locksley, R. M. Regulation of immune responses by tuft cells. Nat. Rev. Immunol. 19, 584–593 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Herring, C. A. et al. Unsupervised trajectory analysis of single-cell RNA-seq and imaging data reveals alternative tuft cell origins in the gut. Cell Syst. 6, 37–51.e9 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. 135.

    Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647–675 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    von Moltke, J., Ji, M., Liang, H.-E. & Locksley, R. M. Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit. Nature 529, 221–225 (2015).

    Article  CAS  Google Scholar 

  137. 137.

    Goto, N. et al. Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 116, 12996–13005 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  138. 138.

    Gracz, A. D. et al. Sox4 promotes Atoh1-independent intestinal secretory differentiation toward tuft and enteroendocrine fates. Gastroenterology 155, 1508–1523.e10 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Gehart, H. et al. Identification of enteroendocrine regulators by real-time single-cell differentiation mapping. Cell 176, 1158–1173.e16 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Kazanjian, A., Noah, T., Brown, D., Burkart, J. & Shroyer, N. F. Atonal homolog 1 is required for growth and differentiation effects of Notch/γ-secretase inhibitors on normal and cancerous intestinal epithelial cells. Gastroenterology 139, 918–928 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Kim, T. H. & Shivdasani, R. A. Genetic evidence that intestinal Notch functions vary regionally and operate through a common mechanism of Math1 repression. J. Biol. Chem. 286, 11427–11433 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Lindeboom, R. G. et al. Integrative multi-omics analysis of intestinal organoid differentiation. Mol. Syst. Biol. 14, e8227 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143.

    Chen, L. et al. A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity. Nat. Genet. 51, 777–785 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Knoop, K. A. et al. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. J. Immunol. 183, 5738–5747 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Kanaya, T. et al. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat. Immunol. 13, 729–736 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Lai, N. Y. et al. Gut-Innervating nociceptor neurons regulate Peyer’s patch microfold cells and SFB levels to mediate salmonella host defense. Cell 180, 33–49.e22 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  147. 147.

    Moor, A. E. et al. Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis. Cell 175, 1156–1167.e15 (2018). Moor et al. describe profound transcriptomic changes along the villus axis of mice, revealing dynamic functions of cell types over their lifetime.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 148.

    Halpern, K. B. et al. Lgr5+ telocytes are a signaling source at the intestinal villus tip. Nat. Commun. 11, 1936 (2020).

    Article  CAS  Google Scholar 

  149. 149.

    Aiken, K. D., Kisslinger, J. A. & Roth, K. A. Immunohistochemical studies indicate multiple enteroendocrine cell differentiation pathways in the mouse proximal small intestine. Dev. Dyn. 201, 63–70 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Roth, K. A. & Gordon, J. I. Spatial differentiation of the intestinal epithelium: analysis of enteroendocrine cells containing immunoreactive serotonin, secretin, and substance P in normal and transgenic mice. Proc. Natl Acad. Sci. USA 87, 6408–6412 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Beumer, J. et al. Enteroendocrine cells switch hormone expression along the crypt-to-villus BMP signalling gradient. Nat. Cell Biol. 20, 909–916 (2018). Beumer et al. demonstrate the plasticity of intestinal hormone-producing cells and its dependence on a BMP signalling gradient.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Billing, L. J. et al. Single cell transcriptomic profiling of large intestinal enteroendocrine cells in mice – identification of selective stimuli for insulin-like peptide-5 and glucagon-like peptide-1 co-expressing cells. Mol. Metab. 29, 158–169 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Clevers, H. & Nusse, R. Wnt/B-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    van Es, J. H. et al. A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic self-renewal. Mol. Cell. Biol. 32, 1918–1927 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. 155.

    Korinek, V. et al. Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse. Mol. Cell. Biol. 18, 1248–1256 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Kuhnert, F. et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl Acad. Sci. USA 101, 266–271 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 159.

    Hao, H.-X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–200 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160.

    Spit, M., Koo, B. K. & Maurice, M. M. Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer. Open Biol. 8, 180120 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  161. 161.

    Seshagiri, S. et al. Recurrent R-spondin fusions in colon cancer. Nature 488, 660–664 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Bray, S. J. Notch signalling in context. Nat. Rev. Mol. Cell Biol. 17, 722–735 (2016).

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Wang, R. N. et al. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis. 1, 87–105 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Kosinski, C. et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc. Natl Acad. Sci. USA 104, 15418–15423 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  165. 165.

    Haramis, A. P. G. et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684–1686 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  166. 166.

    He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat. Genet. 36, 1117–1121 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  167. 167.

    Qi, Z. et al. BMP restricts stemness of intestinal Lgr5+ stem cells by directly suppressing their signature genes. Nat. Commun. 8, 13824 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Snippert, H. J., Schepers, A. G., Van Es, J. H., Simons, B. D. & Clevers, H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 15, 62–69 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  169. 169.

    Secor, S. M., Stein, E. D. & Diamond, J. Rapid upregulation of snake intestine in response to feeding: a new model of intestinal adaptation. Am. J. Physiol. 266, G695–G705 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Igarashi, M. & Guarente, L. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell 166, 436–450 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  171. 171.

    Yilmaz, Ö. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Zhou, Y., Rychahou, P., Wang, Q., Weiss, H. L. & Evers, B. M. TSC2/mTORC1 signaling controls Paneth and goblet cell differentiation in the intestinal epithelium. Cell Death Dis. 6, e1631 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Rodríguez-Colman, M. J. et al. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature 543, 424–427 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  174. 174.

    Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Wang, B. et al. Phospholipid remodeling and cholesterol availability regulate intestinal stemness and tumorigenesis. Cell Stem Cell 22, 206–220.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Fu, T. et al. FXR regulates intestinal cancer stem cell proliferation. Cell 176, 1098–1112.e18 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Cheng, C. W. et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 178, 1115–1131.e15 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Koehler, J. A. et al. GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell Metab. 21, 379–391 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  179. 179.

    Koopmann, M. C., Chen, X., Holst, J. J. & Ney, D. M. Sustained glucagon-like peptide-2 infusion is required for intestinal adaptation, and cessation reverses increased cellularity in rats with intestinal failure. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G1222–G1230 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Dahly, E. M. et al. Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G670–G682 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    D’Souza, B., Miyamoto, A. & Weinmaster, G. The many facets of Notch ligands. Oncogene 27, 5148–5167 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank J. Puschhof for critical reading of the manuscript.

Author information

Affiliations

Authors

Contributions

J.B. wrote the first draft of the manuscript; H.C. was involved in the discussion of content and at all stages of revision.

Corresponding author

Correspondence to Hans Clevers.

Ethics declarations

Competing interests

H.C. is the inventor on several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. H.C. is the founder of OrganoidZ, which uses organoids for drug development. J.B. declares no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks Kim Jensen, Cédric Blanpain and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Genetic lineage tracing

Developmental tool to identify the progeny of a single cell through the introduction of a genetic marker in an individual (stem) cell.

Chemical mutagenesis labelling

Marking random cells through chemical induction of mutations in a traceable locus to study stem cell dynamics and clonal succession. All intestinal epithelial cells are stained by the Dolichos biflorus agglutinin lectin, but this is lost by random mutations in the Dlb1 (also known as B4galnt2) locus, allowing the study of clonal dynamics.

Telomerase

Ribonucleoprotein and reverse transcriptase that can add telomere repeat sequences to the end of telomeres.

R-spondin

Secreted enhancer of the WNT signalling pathway acting through cognate leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4), LGR5 and LGR6.

Stem cell factors

Instructive signals that dictate stem cell proliferation and the balance between multipotency and lineage commitment.

Neutral drift

Model in which equipotent stem cells neutrally compete for niche space, which over time results in clonal crypts.

ErbB

ErbB family members are tyrosine kinase receptors that dimerize on ligand (such as epidermal growth factor (EGF)) engagement, activating downstream signalling. EGF–ErbB signalling is a main player in the control of intestinal proliferation.

proEGF

Precursor that is processed to epithelial growth factor (EGF) through proteolytic cleavage.

Colitis

Inflammation of the intestine causing epithelial damage often with a strong autoimmune component.

Helminth

A parasitic worm that can infect the intestinal tract, a condition called ‘helminthiasis’.

Granulomatous infiltrates

A histological pattern of infection containing circular granulomas harbouring different immune cells. In the context of helminth infection, these can develop to control parasite spreading.

Spheroids

Three-dimensional culture of a homogeneous cell population (typically from a cell line). When the 3D structures harbour different organ-specific cell types, these are generally referred to as ‘organoids’.

Anoikis

The process of programmed cell death that occurs when epithelial cells lose contact with the surrounding extracellular matrix.

Neural crest

Group of cells emanating from the embryonic neurectoderm during development that develop through complex migration patterns into a wide variety of cell types, including melanocytes, smooth muscle and the enteric nervous system.

Piezo channels

Class of mechanosensitive ion channels that acts as gates depending on mechanical stimuli on the cell membrane.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Beumer, J., Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat Rev Mol Cell Biol (2020). https://doi.org/10.1038/s41580-020-0278-0

Download citation

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing