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.

Tissue-specific designs of stem cell hierarchies

Nature Cell Biology volume 18, pages 349–355 (2016)Cite this article

Subjects

Abstract

Recent work in the field of stem cell biology suggests that there is no single design for an adult tissue stem cell hierarchy, and that different tissues employ distinct strategies to meet their self-renewal and repair requirements. Stem cells may be multipotent or unipotent, and can exist in quiescent or actively dividing states. 'Professional' stem cells may also co-exist with facultative stem cells, which are more specialized daughter cells that revert to a stem cell state under specific tissue damage conditions. Here, we discuss stem cell strategies as seen in three solid mammalian tissues: the intestine, mammary gland and skeletal muscle.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Schematic structures of the small intestine, mammary epithelial tree and skeletal muscle, and the location of their stem cells.
Figure 2: Schematic models of stem cell hierarchies in the small intestine, mammary gland and skeletal muscle.
Figure 3: A general model depicting the hierarchical organization of tissue-specific stem and progenitor cells.

References

  1. Chao, M. P., Seita, J. & Weissman, I. L. Establishment of a normal hematopoietic and leukemia stem cell hierarchy. Cold Spring Harb. Symp. Quant. Biol. 73, 439–449 (2008).

    CAS  PubMed  Google Scholar 

  2. Eaves, C. J. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood 125, 2605–2613 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Choi, N., Zhang, B., Zhang, L., Ittmann, M. & Xin, L. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 21, 253–265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011).

    CAS  PubMed  Google Scholar 

  5. Wang, Z. A. et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat. Cell Biol. 15, 274–283 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Barbera, M. et al. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut 64, 11–19 (2015).

    PubMed  Google Scholar 

  7. DeWard, A. D., Cramer, J. & Lagasse, E. Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep. 9, 701–711 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hsu, Y. C., Li, L. & Fuchs, E. Emerging interactions between skin stem cells and their niches. Nat. Med. 20, 847–856 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tetteh, P. W., Farin, H. F. & Clevers, H. Plasticity within stem cell hierarchies in mammalian epithelia. Trends Cell Biol. 25, 100–108 (2015).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Bjerknes, M. & Cheng, H. The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. Am. J. Anat. 160, 51–63 (1981).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. 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  Google Scholar 

  14. Winton, D. J. & Ponder, B. A. Stem-cell organization in mouse small intestine. Proc. Biol. Sci. 241, 13–18 (1990).

    CAS  PubMed  Google Scholar 

  15. 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  Google Scholar 

  16. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. 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  Google Scholar 

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

    PubMed  Google Scholar 

  20. 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  Google Scholar 

  21. 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  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 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  Google Scholar 

  26. Grun, D. et al. Single-cell messenger RNA sequencing reveals rare intestinal cell types. Nature 525, 251–255 (2015).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  29. Wong, V. W. 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  Google Scholar 

  30. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Stamataki, D. et al. Delta1 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat. Cell Biol. 14, 1099–1104 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Basak, O. et al. Mapping early fate determination in Lgr5+ crypt stem cells using a novel Ki67-RFP allele. EMBO J. 33, 2057–2068 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, F. et al. Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 145, 383–395 (2013).

    CAS  PubMed  Google Scholar 

  36. Buczacki, S. J. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 65–69 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Daniel, C. W., De Ome, K. B., Young, J. T., Blair, P. B. & Faulkin, L. J., Jr. The in vivo life span of normal and preneoplastic mouse mammary glands: a serial transplantation study. Proc. Natl Acad. Sci. USA 61, 53–60 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Hoshino, K. Morphogenesis and growth potentiality of mammary glands in mice: transplantability and growth potentiality of mammary tissue of virgin mice. J. Natl Cancer Inst. 29, 835–851 (1962).

    CAS  PubMed  Google Scholar 

  40. Smith, G. H. & Medina, D. A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland. J. Cell Sci. 90, 173–183 (1988).

    PubMed  Google Scholar 

  41. Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006).

    CAS  PubMed  Google Scholar 

  42. Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006).

    CAS  PubMed  Google Scholar 

  43. Dos Santos, C. O. et al. Molecular hierarchy of mammary differentiation yields refined markers of mammary stem cells. Proc. Natl Acad. Sci. USA 110, 7123–7130 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Boras-Granic, K., Dann, P. & Wysolmerski, J. J. Embryonic cells contribute directly to the quiescent stem cell population in the adult mouse mammary gland. Breast Cancer Res. 16, 487 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009).

    CAS  PubMed  Google Scholar 

  46. Asselin-Labat, M. L. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 465, 798–802 (2010).

    CAS  PubMed  Google Scholar 

  47. Stingl, J., Eaves, C. J., Zandieh, I. & Emerman, J. T. Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue. Breast Cancer Res. Treat. 67, 93–109 (2001).

    CAS  PubMed  Google Scholar 

  48. Visvader, J. E. & Stingl, J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 28, 1143–1158 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. van Amerongen, R., Bowman, A. N. & Nusse, R. Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 11, 387–400 (2012).

    CAS  PubMed  Google Scholar 

  50. Rios, A. C., Fu, N. Y., Lindeman, G. J. & Visvader, J. E. In situ identification of bipotent stem cells in the mammary gland. Nature 506, 322–327 (2014).

    CAS  PubMed  Google Scholar 

  51. Tao, L., van Bragt, M. P., Laudadio, E. & Li, Z. Lineage tracing of mammary epithelial cells using cell-type-specific cre-expressing adenoviruses. Stem Cell Rep. 2, 770–779 (2014).

    CAS  Google Scholar 

  52. Prater, M. D. et al. Mammary stem cells have myoepithelial cell properties. Nat. Cell Biol. 16, 942–950 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, D. et al. Identification of multipotent mammary stem cells by protein C receptor expression. Nature 517, 81–84 (2015).

    CAS  PubMed  Google Scholar 

  54. Nguyen, L. V. et al. Clonal analysis via barcoding reveals diverse growth and differentiation of transplanted mouse and human mammary stem cells. Cell Stem Cell 14, 253–263 (2014).

    CAS  PubMed  Google Scholar 

  55. Lafkas, D. et al. Notch3 marks clonogenic mammary luminal progenitor cells in vivo. J. Cell Biol. 203, 47–56 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Rodilla, V. et al. Luminal progenitors restrict their lineage potential during mammary gland development. PLoS Biol. 13, e1002069 (2015).

    PubMed  PubMed Central  Google Scholar 

  57. de Visser, K. E. et al. Developmental stage-specific contribution of LGR5+ cells to basal and luminal epithelial lineages in the postnatal mammary gland. J. Pathol. 228, 300–309 (2012).

    CAS  PubMed  Google Scholar 

  58. Collins, C. A. et al. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122, 289–301 (2005).

    CAS  PubMed  Google Scholar 

  59. Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012).

    CAS  PubMed  Google Scholar 

  60. Sacco, A., Doyonnas, R., Kraft, P., Vitorovic, S. & Blau, H. M. Self-renewal and expansion of single transplanted muscle stem cells. Nature 456, 502–506 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Brack, A. S. & Rando, T. A. Tissue-specific stem cells: lessons from the skeletal muscle satellite cell. Cell Stem Cell 10, 504–514 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Dumont, N. A., Bentzinger, C. F., Sincennes, M. C. & Rudnicki, M. A. Satellite cells and skeletal muscle regeneration. Compr. Physiol. 5, 1027–1059 (2015).

    PubMed  Google Scholar 

  63. Sanchez-Gurmaches, J. et al. PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab. 16, 348–362 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Schulz, T. J. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. White, R. B., Bierinx, A. S., Gnocchi, V. F. & Zammit, P. S. Dynamics of muscle fibre growth during postnatal mouse development. BMC Dev. Biol. 10, 21 (2010).

    PubMed  PubMed Central  Google Scholar 

  67. Lepper, C., Conway, S. J. & Fan, C. M. Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature 460, 627–631 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Murphy, M. M., Lawson, J. A., Mathew, S. J., Hucheson, D. A. & Kardon, G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138, 3625–3637 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011).

    CAS  PubMed  Google Scholar 

  70. McCarthy, J. J. et al. Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development 138, 3657–3666 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Lepper, C., Partridge, T. A. & Fan, C. M. An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138, 3639–3646 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuang, S., Kuroda, K., Le Grand, F. & Rudnicki, M. A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Rodgers, J. T. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert . Nature 510, 393–396 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bischoff, R. Proliferation of muscle satellite cells on intact myofibers in culture. Dev. Biol. 115, 129–139 (1986).

    CAS  PubMed  Google Scholar 

  75. Zammit, P. S. et al. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J. Cell Biol. 166, 347–357 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Brohl, D. et al. Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on Notch signals. Dev. Cell 23, 469–481 (2012).

    PubMed  Google Scholar 

  77. Cheung, T. H. & Rando, T. A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013).

    CAS  PubMed  Google Scholar 

  78. Orford, K. W. & Scadden, D. T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat. Rev. Genet. 9, 115–128 (2008).

    CAS  PubMed  Google Scholar 

  79. Walter, D. et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature 520, 549–552 (2015).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank P. Maltezos (WEHI, Melbourne, Australia) for assistance with figure preparation. J.E.V. is supported by a NHMRC Australia Fellowship, and thanks the NHMRC IRIISS, Australian Cancer Research Foundation and National Breast Cancer Foundation.

Author information

Authors and Affiliations

  1. Jane E. Visvader is in the Stem Cells and Cancer Division, and the Department of Medical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia, The University of Melbourne, Parkville, Victoria 3010, Australia,

    Jane E. Visvader

  2. Hans Clevers is at the Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, The Netherlands, and the University Medical Center Utrecht, Cancer Genomics Netherlands, 3584 CG Utrecht, The Netherlands,

    Hans Clevers

Authors
  1. Jane E. Visvader
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Clevers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jane E. Visvader or Hans Clevers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Visvader, J., Clevers, H. Tissue-specific designs of stem cell hierarchies. Nat Cell Biol 18, 349–355 (2016). https://doi.org/10.1038/ncb3332

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb3332

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