Review Article | Published:

Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer

Nature Reviews Genetics volume 19, pages 311325 (2018) | Download Citation

Abstract

Stem cells (SCs) govern tissue homeostasis and wound repair. They reside within niches, the special microenvironments within tissues that control SC lineage outputs. Upon injury or stress, new signals emanating from damaged tissue can divert nearby cells into adopting behaviours that are not part of their homeostatic repertoire. This behaviour, known as SC plasticity, typically resolves as wounds heal. However, in cancer, it can endure. Recent studies have yielded insights into the orchestrators of maintenance and lineage commitment for SCs belonging to three mammalian tissues: the haematopoietic system, the skin epithelium and the intestinal epithelium. We delineate the multifactorial determinants and general principles underlying the remarkable facets of SC plasticity, which lend promise for regenerative medicine and cancer therapeutics.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978). In this paper, the SC niche concept is coined and formally elaborated upon.

  2. 2.

    & A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213–222 (1961). This article presents the discovery of spleen colony-forming units, clonogenic bone marrow precursors that give rise to macroscopic spleen colonies after transplantation into irradiated recipient mice, a work directly leading to the definition of a SC.

  3. 3.

    , , , & Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic system of W/Wv mice. Cell 42, 71–79 (1985).

  4. 4.

    , & Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45, 917–927 (1986).

  5. 5.

    , & Isolation of two early B lymphocyte progenitors from mouse marrow: a committed pre-pre-B cell and a clonogenic Thy-1-lo hematopoietic stem cell. Cell 44, 653–662 (1986).

  6. 6.

    , & Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988). This is the first prospective isolation of HSCs using FACS, which showed that HSCs self-renew and give rise to all blood lineages.

  7. 7.

    & The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).

  8. 8.

    , , , & New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126, 415–426 (2006).

  9. 9.

    , & Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

  10. 10.

    , , & A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

  11. 11.

    et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008). This is the initial demonstration via label retention analysis that HSCs are dormant under steady state and cycle only five times per a mouse's lifetime but contribute significantly to downstream lineage output upon injury.

  12. 12.

    et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84–90 (2009).

  13. 13.

    , , , & Hematopoietic stem cells count and remember self-renewal divisions. Cell 167, 1296–1309 (2016).

  14. 14.

    , , & In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc. Natl Acad. Sci. USA 96, 3120–3125 (1999).

  15. 15.

    , , , & Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J. Exp. Med. 202, 1599–1611 (2005).

  16. 16.

    et al. Clonal dynamics of native haematopoiesis. Nature 514, 322–327 (2014).

  17. 17.

    et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 518, 542–546 (2015). References 16 and 17 used in vivo lineage tracing via endogenous tagging to demonstrate that multipotent progenitors rather than HSCs fuel the steady-state homeostasis.

  18. 18.

    et al. Epigenetic memory underlies cell-autonomous heterogeneous behavior of hematopoietic stem cells. Cell 167, 1310–1322 (2016). By tracing and isolating multifluorescent clones, this study matches molecular profiles with functional output of HSCs and reveals that epigenetic mechanisms underlie HSC intrinsic memory and functional heterogeneity.

  19. 19.

    Endosteal marrow: a rich source of hematopoietic stem cells. Science 199, 1443–1445 (1978).

  20. 20.

    et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457, 97–101 (2009).

  21. 21.

    et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009).

  22. 22.

    et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005). This study discusses simple combinations of lineage markers in FACS distinguished between HSCs and progenitor cells and reveals for the first time the association of HSCs with sinusoidal endothelium in spleen and bone marrow.

  23. 23.

    et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013). This paper describes the illustration of arteriolar endothelium as a HSC niche.

  24. 24.

    , , & Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).

  25. 25.

    & Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013). References 24 and 25 provide direct evidence via cell type-specific gene ablation that endothelial and perivascular cells act as obligatory HSC niches by providing HSC maintenance factors stem cell factor/KIT ligand (KITL) (reference 24) and CXCL12 (reference 25), whereas early lymphoid progenitors are dependent on endosteal CXCL12 (reference 25).

  26. 26.

    et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat. Cell Biol. 12, 1046–1056 (2010).

  27. 27.

    et al. Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell 160, 241–252 (2015).

  28. 28.

    et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126–130 (2015).

  29. 29.

    , , , & Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014).

  30. 30.

    et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33, 387–399 (2010).

  31. 31.

    , , & Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006).

  32. 32.

    , , , & Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell 18, 782–796 (2016).

  33. 33.

    et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat. Cell Biol. 19, 891–903 (2017).

  34. 34.

    et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

  35. 35.

    et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat. Cell Biol. 19, 214–223 (2017).

  36. 36.

    et al. Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548, 456–460 (2017).

  37. 37.

    et al. Clonal fate mapping quantifies the number of haematopoietic stem cells that arise during development. Nat. Cell Biol. 19, 17–27 (2016).

  38. 38.

    et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 474, 216–219 (2011).

  39. 39.

    et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116, 4815–4828 (2010).

  40. 40.

    et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

  41. 41.

    et al. Monocytes-macrophages that express alpha-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow. Nat. Immunol. 13, 1072–1082 (2012).

  42. 42.

    et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 20, 1315–1320 (2014).

  43. 43.

    et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat. Med. 20, 1321–1326 (2014).

  44. 44.

    & Skin and its regenerative powers: an alliance between stem cells and their niche. Dev. Cell 43, 387–401 (2017).

  45. 45.

    , , , & Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell 8, 552–565 (2011).

  46. 46.

    et al. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell 126, 597–609 (2006).

  47. 47.

    et al. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell 4, 427–439 (2009).

  48. 48.

    et al. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development 133, 3027–3037 (2006).

  49. 49.

    et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 327, 1385–1389 (2010).

  50. 50.

    Engineered microenvironments to direct epidermal stem cell behavior at single-cell resolution. Dev. Cell 38, 601–609 (2016).

  51. 51.

    & Switching roles: the functional plasticity of adult tissue stem cells. EMBO J. 34, 1164–1179 (2015).

  52. 52.

    , , , & Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).

  53. 53.

    , , , & Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc. Natl Acad. Sci. USA 102, 14677–14682 (2005). References 52 and 53 are the first to show that cells from the bulge are HFSCs that undergo long-term self-renewal and reconstitute all lineages of the pilosebaceous unit and the epidermis upon engraftment.

  54. 54.

    et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat. Med. 11, 1351–1354 (2005). This study shows that HFSCs of the bulge do not contribute to the interfollicular epidermis under steady state and do so only when subjected to epidermal wounding.

  55. 55.

    , , & Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855–861 (2005).

  56. 56.

    , & Dynamics between stem cells, niche, and progeny in the hair follicle. Cell 144, 92–105 (2011).

  57. 57.

    et al. A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell 4, 155–169 (2009). This study shows that by having a polarized niche stimulus, stem cells become differentially activated, enabling the niche to conserve its residents.

  58. 58.

    , , , & Epithelial-mesenchymal micro-niches govern stem cell lineage choices. Cell 169, 483–496 (2017).

  59. 59.

    , & Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157, 935–949 (2014).

  60. 60.

    et al. Hair follicle stem cells provide a functional niche for melanocyte stem cells. Cell Stem Cell 8, 177–187 (2011).

  61. 61.

    et al. Integrin-linked kinase regulates the niche of quiescent epidermal stem cells. Nat. Commun. 6, 8198 (2015).

  62. 62.

    et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 451, 340–344 (2008).

  63. 63.

    , & Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop. Genes Dev. 26, 1235–1246 (2012).

  64. 64.

    , & Spatial organization within a niche as a determinant of stem-cell fate. Nature 502, 513–518 (2013). This study shows that upon loss of hair follicle bulge SCs via laser ablation, hair germ and upper hair follicle cells in the vicinity can repopulate the emptied niche.

  65. 65.

    , & Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline. Development 140, 1676–1683 (2013).

  66. 66.

    et al. Sox2 in the dermal papilla niche controls hair growth by fine-tuning bmp signaling in differentiating hair shaft progenitors. Dev. Cell 23, 981–994 (2012).

  67. 67.

    et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761–771 (2011).

  68. 68.

    et al. Self-organizing and stochastic behaviors during the regeneration of hair stem cells. Science 332, 586–589 (2011).

  69. 69.

    , , & Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration. J. Invest. Dermatol. 133, 31–41 (2013).

  70. 70.

    , & Macrophages contribute to the cyclic activation of adult hair follicle stem cells. PLoS Biol. 12, e1002002 (2014).

  71. 71.

    et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129 (2017).

  72. 72.

    et al. The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 147, 1615–1627 (2011).

  73. 73.

    & Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. Am. J. Anat. 141, 461–479 (1974).

  74. 74.

    et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007). This study demonstrated that LGR5-expressing cells at the crypt base are intestinal SCs that undergo long-term self-renewal and give rise to all lineages of the crypt–villus.

  75. 75.

    et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009). In this work, the authors pioneer methods to grow, maintain and passage intestinal organoids in vitro from individual SCs.

  76. 76.

    et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011).

  77. 77.

    & Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6, 331–343 (1975).

  78. 78.

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

  79. 79.

    , , & Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J. Biol. Chem. 272, 23729–23740 (1997).

  80. 80.

    et al. Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO Rep. 12, 558–564 (2011).

  81. 81.

    , , , & Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev. 19, 2412–2417 (2005).

  82. 82.

    et al. SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 133, 539–546 (2007).

  83. 83.

    , , & Evidence for a crucial role of paneth cells in mediating the intestinal response to injury. Stem Cells 31, 776–785 (2013).

  84. 84.

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

  85. 85.

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

  86. 86.

    et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 19, 379–383 (1998).

  87. 87.

    , , & Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003).

  88. 88.

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

  89. 89.

    et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat. Cell Biol. 7, 381–386 (2005).

  90. 90.

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

  91. 91.

    et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626–638 (2005).

  92. 92.

    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).

  93. 93.

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

  94. 94.

    , , & Wnt secretion from epithelial cells and subepithelial myofibroblasts is not required in the mouse intestinal stem cell niche in vivo. Stem Cell Rep. 2, 127–134 (2014).

  95. 95.

    et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 141, 2206–2215 (2014).

  96. 96.

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

  97. 97.

    et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476, 293–297 (2011).

  98. 98.

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

  99. 99.

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

  100. 100.

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

  101. 101.

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

  102. 102.

    , , & Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 422, 317–322 (2003).

  103. 103.

    et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013). These authors showed that within the embryonic SC genome are large open chromatin regions that are marked by particularly robust H3K27 acetylation. These super-enhancers are bound cooperatively by the pluripotency transcription factors and regulate key pluripotency genes, forming a feedforward regulatory loop for maintaining the SC state.

  104. 104.

    et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl Acad. Sci. USA 110, 17921–179260 (2013).

  105. 105.

    & The Yin and Yang of chromatin dynamics in stem cell fate selection. Trends Genet. 12, 002 (2015).

  106. 106.

    et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

  107. 107.

    et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

  108. 108.

    et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

  109. 109.

    et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat. Genet. 46, 136–143 (2014).

  110. 110.

    et al. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521, 366–370 (2015). These authors showed that key stemness genes for HFSCs are regulated by super-enhancers, within which are smaller elements, epicentres, that bind the master regulators for these particular SCs and functionally target expression in a niche-dependent manner.

  111. 111.

    et al. Chromatin state dynamics during blood formation. Science 345, 943–949 (2014).

  112. 112.

    et al. Stem cell lineage infidelity drives wound repair and cancer. Cell 169, 636–650 (2017). The authors demonstrate that following injury, skin SCs enter an obligatory transient chromatin state where they survive outside the niche by expressing genes typifying dual epithelial lineages. Following repair, this mechanism for SCs to cope with stress resolves, but in cancer the state is hijacked permanently to fuel malignancy.

  113. 113.

    , , & Temporal layering of signaling effectors drives chromatin remodeling during hair follicle stem cell lineage progression. Cell Stem Cell (2017).

  114. 114.

    et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017).

  115. 115.

    et al. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9, 219–232 (2011).

  116. 116.

    et al. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147, 577–589 (2011). This paper shows that transcription factors that regulate lineage identity and developmental signalling converge on chromatin to regulate cell fate decisions during haematopoiesis.

  117. 117.

    et al. BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages. Cell Stem Cell 15, 619–633 (2014).

  118. 118.

    , , , & NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132, 299–310 (2008).

  119. 119.

    et al. Stem cell plasticity enables hair regeneration following Lgr5+ cell loss. Nat. Cell Biol. 19, 666–676 (2017).

  120. 120.

    , , & Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen. Differentiation 72, 548–557 (2004).

  121. 121.

    & An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells. Proc. Natl Acad. Sci. USA 100, 4633–4638 (2003). This pioneering study shows that in the female ovaries of D. melanogaster, an emptied niche stimulates cellular plasticity.

  122. 122.

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

  123. 123.

    & Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004).

  124. 124.

    & An epithelial niche in the Drosophila ovary undergoes long-range stem cell replacement. Cell Stem Cell 1, 277–285 (2007).

  125. 125.

    , , & Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

  126. 126.

    et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010). References 125 and 126 show that the intestinal SC crypt is regulated through neutral drift, a state where proliferating SCs compete stochastically for a limited number of niche positions.

  127. 127.

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

  128. 128.

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

  129. 129.

    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).

  130. 130.

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

  131. 131.

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

  132. 132.

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

  133. 133.

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

  134. 134.

    , , , & Regeneration of intestinal stem/progenitor cells following doxorubicin treatment of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G461–G470 (2009).

  135. 135.

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

  136. 136.

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

  137. 137.

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

  138. 138.

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

  139. 139.

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

  140. 140.

    et al. Mex3a marks a slowly dividing subpopulation of Lgr5+ intestinal stem cells. Cell Stem Cell 20, 801–816 (2017).

  141. 141.

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

  142. 142.

    et al. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506, 511–515 (2014).

  143. 143.

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

  144. 144.

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

  145. 145.

    , , & Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14, 149–159 (2014).

  146. 146.

    et al. Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary. Cell Stem Cell 2, 39–49 (2008).

  147. 147.

    et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503, 218–223 (2013). This study reveals that when a single lung basal cell is co-cultured with Clara cells, the reversion of Clara cells into basal cells is restricted.

  148. 148.

    et al. Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair. Cell 150, 136–150 (2012). This study reveals that in glandular mouse skin, it is the progenitor closest to the wound site that repairs the injury. The study also shows that a sweat gland SC transplanted into a cleared mammary fat pad can reconstitute a sweat gland, but over time it begins to adopt features dictated by its new microenvironment.

  149. 149.

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

  150. 150.

    , , & Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding. Nat. Biotechnol. 29, 928–933 (2011).

  151. 151.

    , & Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl Acad. Sci. USA 94, 1908–1913 (1997).

  152. 152.

    , , , & Mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure. Blood 102, 1249–1253 (2003).

  153. 153.

    et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009).

  154. 154.

    , , , & The epidermis comprises autonomous compartments maintained by distinct stem cell populations. Cell Stem Cell 13, 471–482 (2013). This study revealed plasticity within cells of the upper hair follicle, which in a wound state, but not normal homeostasis, are able to contribute permanently to the regenerated epidermis.

  155. 155.

    Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 14, 296–304 (2017).

  156. 156.

    & Reserve stem cells: differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract. Sci. Signal. 8, re8 (2015).

  157. 157.

    et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

  158. 158.

    et al. Capturing and profiling adult hair follicle stem cells. Nat. Biotechnol. 22, 411–417 (2004).

  159. 159.

    et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320 (2007).

  160. 160.

    et al. ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas. eLife 4, e10870 (2015).

  161. 161.

    et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl Acad. Sci. USA 102, 9194–9199 (2005).

  162. 162.

    et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014).

  163. 163.

    et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl Acad. Sci. USA 107, 5465–5470 (2010).

  164. 164.

    et al. Nfatc1 orchestrates aging in hair follicle stem cells. Proc. Natl Acad. Sci. USA 110, E4950–E4959 (2013).

  165. 165.

    et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

  166. 166.

    & Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).

  167. 167.

    & Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

  168. 168.

    et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004). References 165–168 advance the concept of a CSC as a cell able to propagate a cancer long term and through serial passaging in vivo.

  169. 169.

    , & Epigenetic reprogramming in cancer. Science 339, 1567–1570 (2013).

  170. 170.

    et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004).

  171. 171.

    et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006).

  172. 172.

    & Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10, 257–268 (2006).

  173. 173.

    et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

  174. 174.

    et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl Acad. Sci. USA 108, 7431–7436 (2011). References 173 and 174 use in vivo lineage tracing to reveal that intestinal cancers (reference 173) and SCCs of the skin (reference 174) can derive from an increased tumour burden on their normal SC counterparts.

  175. 175.

    et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 21, 62–70 (2015).

  176. 176.

    et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).

  177. 177.

    et al. Cell-type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition. Cell Stem Cell 20, 191–204 (2016).

  178. 178.

    et al. Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells. Nat. Commun. 7, 12166 (2016).

  179. 179.

    & Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-beta and integrin/focal adhesion kinase (FAK) signaling. Proc. Natl Acad. Sci. USA 108, 10544–10549 (2011).

  180. 180.

    , & TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell 160, 963–976 (2015).

  181. 181.

    et al. TGF-beta-induced quiescence mediates chemoresistance of tumor-propagating cells in squamous cell carcinoma. Cell Stem Cell 21, 650–664 (2017).

  182. 182.

    , , & Differentiation of the major human tumor groups using conventional and monoclonal antibodies specific for individual intermediate filament proteins. Ann. NY Acad. Sci. 455, 649–668 (1985).

  183. 183.

    et al. Coexpression of normally incompatible developmental pathways in retinoblastoma genesis. Cancer Cell 20, 260–275 (2011).

  184. 184.

    et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat. Genet. 48, 1193–1203 (2016).

  185. 185.

    et al. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell 7, 127–133 (2010).

  186. 186.

    & Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia 24, 1844–1851 (2010).

  187. 187.

    et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 543, 676–680 (2017).

  188. 188.

    et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).

  189. 189.

    et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).

  190. 190.

    et al. Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discov. 7, 736–749 (2017).

  191. 191.

    et al. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342, 1226–1230 (2013). This study suggests that within the epidermis, SCs self-renew through WNT signals that are produced by the SCs themselves.

  192. 192.

    , , , & BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors. Development 143, 764–773 (2016).

  193. 193.

    & On the origin of the term “stem cell”. Cell Stem Cell 1, 35–38 (2007).

  194. 194.

    , & Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197, 452–454 (1963).

  195. 195.

    , , & Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

  196. 196.

    , , , & Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 3, 364–366 (2008).

  197. 197.

    et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007).

  198. 198.

    et al. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527, 466–471 (2015).

  199. 199.

    et al. β-Catenin activation regulates tissue growth non-cell autonomously in the hair stem cell niche. Science 343, 1353–1356 (2014).

  200. 200.

    , & Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329–1337 (1990).

  201. 201.

    & Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen. J. Invest. Dermatol. 112, 470–475 (1999).

  202. 202.

    , , , & Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000).

  203. 203.

    Hematopoietic stem/progenitor cell mobilization. A continuing quest for etiologic mechanisms. Ann. NY Acad. Sci. 872, 187–197 (1999).

  204. 204.

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

  205. 205.

    et al. Proximity-based differential single-cell analysis of the niche to identify stem/progenitor cell regulators. Cell Stem Cell 19, 530–543 (2016).

  206. 206.

    et al. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J. Clin. Invest. 116, 2808–2816 (2006).

  207. 207.

    & Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat. Rev. Genet. 9, 115–128 (2008).

  208. 208.

    et al. Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449, 238–242 (2007).

  209. 209.

    , , & Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. Mol. Biol. Cell 17, 3051–3061 (2006).

  210. 210.

    et al. Defining the cellular lineage hierarchy in the interfollicular epidermis of adult skin. Nat. Cell Biol. 18, 619–631 (2016).

  211. 211.

    , & Wnt regulates spindle asymmetry to generate asymmetric nuclear beta-catenin in C. elegans. Cell 146, 942–954 (2011).

  212. 212.

    & Polarized Wnt signaling regulates ectodermal cell fate in Xenopus. Dev. Cell 29, 250–257 (2014).

  213. 213.

    & Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

  214. 214.

    , , , & WNT-SHH antagonism specifies and expands stem cells prior to niche formation. Cell 164, 156–169 (2016).

  215. 215.

    et al. A localized Wnt signal orients asymmetric stem cell division in vitro. Science 339, 1445–1448 (2013).

  216. 216.

    , & Coupling organelle inheritance with mitosis to balance growth and differentiation. Science 355, eaah4701 (2017).

  217. 217.

    , , & The segregation of DNA in epithelial stem cells. Cell 15, 899–906 (1978).

  218. 218.

    , , & Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat. Cell Biol. 8, 677–687 (2006).

  219. 219.

    , & High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol. 5, e102 (2007).

  220. 220.

    et al. Quantitative proliferation dynamics and random chromosome segregation of hair follicle stem cells. EMBO J. 27, 1309–1320 (2008).

  221. 221.

    et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat. Genet. 40, 1291–1299 (2008).

  222. 222.

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

  223. 223.

    et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat. Cell Biol. 12, 299–305 (2010).

  224. 224.

    et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc. Natl Acad. Sci. USA 108, 7425–7430 (2011).

  225. 225.

    , , & Basal cell carcinomas arise from hair follicle stem cells in Ptch1(+/−) mice. Cancer Cell 19, 114–124 (2011).

  226. 226.

    et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell. 18, 510–523 (2010).

  227. 227.

    et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7, 403–417 (2010).

  228. 228.

    , & A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proc. Natl Acad. Sci. USA 51, 29–36 (1964).

  229. 229.

    , & The identification in adult bone marrow of pluripotent and restricted stem cells of the myeloid and lymphoid systems. J. Exp. Med. 145, 1567–1579 (1977).

  230. 230.

    & Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl Acad. Sci. USA 98, 14541–14546 (2001).

  231. 231.

    , , , & Separation of pluripotent haematopoietic stem cells from spleen colony-forming cells. Nature 347, 188–189 (1990).

  232. 232.

    , , & Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).

  233. 233.

    , , & Hematopoietic stem cells engraft in mice with absolute efficiency. Nat. Immunol. 4, 708–713 (2003).

  234. 234.

    , , , & Hematopoietic stem cells do not engraft with absolute efficiencies. Blood 107, 501–507 (2006).

  235. 235.

    et al. Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. Dev. Cell. 8, 907–914 (2005).

  236. 236.

    , & Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J. Exp. Med. 207, 1173–1182 (2010).

  237. 237.

    et al. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 1, 218–229 (2007).

  238. 238.

    , , & Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002).

  239. 239.

    et al. The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood 107, 2311–2316 (2006).

  240. 240.

    , , , & Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment. Nat. Immunol. 7, 1225–1233 (2006).

  241. 241.

    & Clonal and systemic analysis of long-term hematopoiesis in the mouse. Genes Dev. 4, 220–232 (1990).

  242. 242.

    et al. Hematopoietic stem cells expressing the myeloid lysozyme gene retain long-term, multilineage repopulation potential. Immunity 19, 689–699 (2003).

  243. 243.

    Priming the hematopoietic pump. Immunity 19, 633–634 (2003).

  244. 244.

    et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 351, aab2116 (2016).

  245. 245.

    et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol. 19, 271–281 (2017).

  246. 246.

    et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015).

  247. 247.

    et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 15, 507–522 (2014).

  248. 248.

    et al. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell 17, 35–46 (2015).

  249. 249.

    , & SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell 13, 102–116 (2013).

  250. 250.

    et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature 502, 232–236 (2013).

  251. 251.

    et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell 154, 1112–1126 (2013).

  252. 252.

    et al. MOZ (KAT6A) is essential for the maintenance of classically defined adult hematopoietic stem cells. Blood 128, 2307–2318 (2016).

  253. 253.

    et al. The bulk of the hematopoietic stem cell population is dispensable for murine steady-state and stress hematopoiesis. Blood 128, 2285–2296 (2016).

  254. 254.

    et al. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 105, 2340–2342 (2005).

  255. 255.

    et al. Simultaneous loss of beta- and gamma-catenin does not perturb hematopoiesis or lymphopoiesis. Blood 111, 160–164 (2008).

  256. 256.

    et al. Long-term, multilineage hematopoiesis occurs in the combined absence of beta-catenin and gamma-catenin. Blood 111, 142–149 (2008).

  257. 257.

    et al. Distinct functions for Wnt/beta-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13, 720–733 (2013).

  258. 258.

    et al. In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators. Nat. Cell Biol. 16, 179–190 (2014).

  259. 259.

    et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 327, 1650–1653 (2010).

  260. 260.

    , & The cancer genome. Nature 458, 719–724 (2009).

  261. 261.

    et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

  262. 262.

    & Lessons from the cancer genome. Cell 153, 17–37 (2013).

  263. 263.

    & A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

  264. 264.

    et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl Med. 4, 149ra118 (2012).

  265. 265.

    , , , & Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc. Natl Acad. Sci. USA 111, 2548–2553 (2014).

  266. 266.

    , , , & Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).

  267. 267.

    , & Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc. Natl Acad. Sci. USA 110, 1999–2004 (2013).

  268. 268.

    et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

  269. 269.

    , & Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968 (1953).

  270. 270.

    et al. Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J. Clin. Invest. 100, 2133–2137 (1997).

  271. 271.

    , , & p53-mutant clones and field effects in Barrett's esophagus. Cancer Res. 59, 4784–4787 (1999).

  272. 272.

    , , & Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases. Int. J. Cancer 99, 549–554 (2002).

  273. 273.

    , , & Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: a local field effect of genomic instability and clonal evolution. Genes Chromosomes Cancer 24, 127–134 (1999).

  274. 274.

    et al. Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. Cancer Res. 58, 5835–5841 (1998).

  275. 275.

    et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA 93, 14025–14029 (1996).

  276. 276.

    et al. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nat. Cell Biol. 16, 615–622 (2014).

  277. 277.

    et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).

  278. 278.

    et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

  279. 279.

    et al. p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell 158, 579–592 (2014).

Download references

Acknowledgements

The authors thank R. C. Adam, M. Laurin and S. Ellis for discussions and critical feedback of the manuscript. This work was supported by grants from the National Institutes of Health (AR05042). Y.G. is an awardee of Robertson Therapeutic Development Fund. E.F. is an investigator of the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.

    • Yejing Ge
    •  & Elaine Fuchs

Authors

  1. Search for Yejing Ge in:

  2. Search for Elaine Fuchs in:

Contributions

The authors contributed equally to all aspects of the article.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Elaine Fuchs.

Glossary

Totipotency

The ability of a zygote to give rise to all the lineages of the embryo and extra-embryonic tissues. It differs from the ability of embryonic stem cells to generate all lineages of the embryo (pluripotency) and the ability of adult stem cells to reconstitute multiple (multipotency), a few selective (oligopotency) or a single lineage (unipotency) of a tissue.

Plasticity

In this Review, any process that is distinct from homeostasis. For example, the increased differentiation of haematopoietic stem cells (HSCs) into cells of all blood lineages upon injury is in sharp contrast to their homeostatic behaviour, where HSCs contribute minimally; therefore, we consider such behaviour to be plastic. Plasticity is not restricted to stem cells, although this Review focuses primarily on stem cell plasticity.

Stemness

The unique ability of stem cells to undergo long-term self-renewal and multilineage differentiation.

Engraftment

A procedure in which transplantation of a stem cell of interest is grafted into a host recipient animal to test for the ability of the cell to contribute to host tissue regeneration.

Epicentres

DNA regulatory elements of about 1 kb in length that sit within broad chromatin domains marked by histone 3 lysine 27 acetylation, so-called super-enhancers or stretch-enhancers and are bound by clustered cell identity and/or stress-specific transcription factors.

Lineage infidelity

A term initially used in blood malignancies to describe the presence of multiple differentiation markers specific to distinct lineages in the same cell. In epithelial wounding, lineage infidelity was observed for skin stem cells, which were found to co-express markers of otherwise confined lineages and functionally rely upon them to cope with stress and mediate repair. Lineage infidelity occurs transiently during wound repair but is hijacked by squamous cell carcinoma where it becomes sustained and is essential for malignancy.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrg.2018.9