Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Dll1+ secretory progenitor cells revert to stem cells upon crypt damage

Nature Cell Biology volume 14, pages 1099–1104 (2012)Cite this article

Subjects

Abstract

Lgr5+ intestinal stem cells generate enterocytes and secretory cells. Secretory lineage commitment requires Notch silencing. The Notch ligand Dll1 is expressed by a subset of immediate stem cell daughters. Lineage tracing in Dll1GFP–ires–CreERT2 knock-in mice reveals that single Dll1high cells generate small, short-lived clones containing all four secretory cell types. Lineage specification thus occurs in immediate stem cell daughters through Notch lateral inhibition. Cultured Dll1high cells form long-lived organoids (mini-guts) on brief Wnt3A exposure. When Dll1high cells are genetically marked before tissue damage, stem cell tracing events occur. Thus, secretory progenitors exhibit plasticity by regaining stemness on damage.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dll1 expression by rare undifferentiated transit-amplifying cells above the Paneth/stem cell zone.
Figure 2: Lineage tracing in the intestine of the Dll1GFP–ires–CreERT2–R26RLacZ mice.
Figure 3: Intestinal Dll1+ cells are secretory lineage precursors.
Figure 4: Dll1 precursors can convert to intestinal stem cells in vitro.
Figure 5: Dll1 precursors can convert into intestinal stem cells in vivo.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  Google Scholar 

  2. Marshman, E., Booth, C. & Potten, C. S. The intestinal epithelial stem cell. Bioessays. 24, 91–98 (2002).

    Article  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Cheng, H. & Leblond, C. P. Origin differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. Am. J. Anat. 141, 461–479 (1974).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Cheng, H. & Leblond, C. P. 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).

    Article  CAS  Google Scholar 

  7. Ireland, H., Houghton, C., Howard, L. & Winton, D. J. Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. Dev. Dynam. 233, 1332–1336 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. 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. 4, 377–383 (2008).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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, 8 (2010).

    Article  Google Scholar 

  15. Milano, J. et al. Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci. 82, 341–358 (2004).

    Article  CAS  Google Scholar 

  16. Wu, Y. et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 464, 1052–1057 (2010).

    Article  CAS  Google Scholar 

  17. Pellegrinet, L. et al. Dll1- and dll4-mediated Notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140, 1230–1240 (2011).

    Article  CAS  Google Scholar 

  18. Crosnier, C. et al. Dll-Notch signalling controls commitment to a secretory fate in the zebrafish intestine. Development. 132, 1093–1104 (2005).

    Article  CAS  Google Scholar 

  19. Beckers, J. et al. Expression of the mouse Dll1 gene during organogenesis and fetal development. Mech. Dev. 84, 165–168 (1999).

    Article  CAS  Google Scholar 

  20. Stamataki, D. et al. Dll1 expression, cell cycle exit, and commitment to a specific secretory fate coincide within a few hours in the mouse intestinal stem cell system. PLoS One. 6, e24484 (2011).

    Article  CAS  Google Scholar 

  21. Von Furstenberg, R. J. et al. Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells. Am. J. Physiol. Gastrointest Liver Physiol. 300, G409–G417 (2011).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. 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 137, 15–17 (2009).

    Article  Google Scholar 

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

    Article  Google Scholar 

  28. Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).

    Article  CAS  Google Scholar 

  29. Ireland, H. et al. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of β-catenin. Gastroenterology 126, 1236–1246 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Raj, A., van den Bogaard, P., Rifkin, S. A., van Oudenaarden, A. & Tyagi, S. Imaging individual mRNA molecules using multiple singly labeled probes. Nat. Methods 10, 877–879 (2008).

    Article  Google Scholar 

  32. Itzkovitz, S. et al. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat. Cell Biol. 14, 106–114 (2011).

    Article  Google Scholar 

  33. 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).

    Article  CAS  Google Scholar 

  34. Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  Google Scholar 

  35. Axelrod, J. D. Delivering the lateral inhibition punch line: it’s all about the timing. Sci. Signal. 3, pe38 (2010).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Kai, T. et al. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004).

    Article  CAS  Google Scholar 

  38. Brawley, C. & Matunis, E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304, 1331–1334 (2004).

    Article  CAS  Google Scholar 

  39. Davies, E. J., Marsh, V. & Clarke, A. R. Origin and maintenance of the intestinal cancer stem cell. Mol. Carcinog 50, 254–263 (2011).

    Article  CAS  Google Scholar 

  40. Anderson, E. C., Hessman, C., Levin, T. G., Monroe, M. M. & Wong, M. H. The role of colorectal cancer stem cells in metastatic disease and therapeutic response. Cancers 3, 319–339 (2011).

    Article  Google Scholar 

  41. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 57, 608–611 (2009).

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by KWF/HUBR2005-3237 (T.S.), KWF/HUBR2005-3956 (L.Z.), EU/Health-F4-2007-200720 (M.v.d.W.), NIH/NCI Physical Sciences Oncology Center at MIT: U54CA143874 (A.L. and A.v.O.), TI Pharma T3-106 (J.H.v.E. and M.v.d.B.) and NIRM (N.S.).

We thank D. Stange for critically reading the manuscript.

Author information

Author notes

  1. Johan H. van Es and Toshiro Sato: These authors contributed equally to this work

Authors and Affiliations

  1. Hubrecht Institute for Developmental Biology and Stem Cell Research & University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, Netherlands

    Johan H. van Es, Toshiro Sato, Marc van de Wetering, Nobuo Sasaki, Laura Zeinstra, Maaike van den Born, Jeroen Korving & Hans Clevers

  2. Department of Physics & Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    Anna Lyubimova & Alexander van Oudenaarden

  3. Institute of Medical Biology, 06-06 Immunos, Singapore

    Annie Ng Yee Nee & Nick Barker

  4. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada

    Alex Gregorieff

  5. Department of Immunology, UMC Utrecht, 3508AB Utrecht, PO Box 85090, Netherlands

    Anton C. M. Martens

  6. Department of Cell Biology, UMC Utrecht, 3508AB Utrecht, PO Box 85090, Netherlands

    Anton C. M. Martens

Authors
  1. Johan H. van Es
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiro Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc van de Wetering
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Lyubimova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annie Ng Yee Nee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alex Gregorieff
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nobuo Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Laura Zeinstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maaike van den Born
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jeroen Korving
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anton C. M. Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nick Barker
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alexander van Oudenaarden
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hans Clevers
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.H.v.E., T.S. and H.C. conceived and designed the experiments, J.H.v.E., T.S., M.v.d.W., A.L., A.G. L.Z., M.v.d.B., J.K., A.C.M.M., A.v.O., N.B. and A.N.Y.N. performed the experiments, J.H.v.E., T.S. M.v.d.W., A.L., A.v.O. and H.C. analysed the data, J.H.E. and H.C. wrote the paper.

Corresponding author

Correspondence to Hans Clevers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 875 kb)

Supplementary Table 1

Supplementary Information (XLS 54 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Es, J., Sato, T., van de Wetering, M. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14, 1099–1104 (2012). https://doi.org/10.1038/ncb2581

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2581

This article is cited by

Search

Advanced search

Quick links

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