A matter of life and death: stem cell survival in tissue regeneration and tumour formation

Abstract

In recent years, great strides have been made in our understanding of how stem cells (SCs) govern tissue homeostasis and regeneration. The inherent longevity of SCs raises the possibility that the unique protective mechanisms in these cells might also be involved in tumorigenesis. In this Opinion article, we discuss how SCs are protected throughout their lifespan, focusing on quiescent behaviour, DNA damage response and programmed cell death. We briefly examine the roles of adult SCs and progenitors in tissue repair and tumorigenesis and explore how signals released from dying or dormant cells influence the function of healthy or aberrant SCs. Important insight into the mechanisms that regulate SC death and survival, as well as the 'legacy' imparted by departing cells, may unlock novel avenues for regenerative medicine and cancer therapy.

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Figure 1: Adult stem cell niches.
Figure 2: A stem cell perspective of wound healing versus tumour formation.
Figure 3: The DNA damage response.
Figure 4: The extrinsic and intrinsic apoptotic pathways.
Figure 5: Signals emanating from dying and dormant cells in model organisms.

References

  1. 1

    Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Mandal, P. K., Blanpain, C. & Rossi, D. J. DNA damage response in adult stem cells: pathways and consequences. Nat. Rev. Mol. Cell Biol. 12, 198–202 (2011).

    CAS  PubMed  Google Scholar 

  3. 3

    Nguyen, L. V., Vanner, R., Dirks, P. & Eaves, C. J. Cancer stem cells: an evolving concept. Nat. Rev. Cancer 12, 133–143 (2012).

    CAS  Google Scholar 

  4. 4

    Blanpain, C. Tracing the cellular origin of cancer. Nat. Cell Biol. 15, 126–134 (2013).

    CAS  PubMed  Google Scholar 

  5. 5

    Ge, Y. et al. Stem cell lineage infidelity drives wound repair and cancer. Cell 169, 636–650 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

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

    CAS  PubMed  Google Scholar 

  7. 7

    Solanas, G. & Benitah, S. A. Regenerating the skin: a task for the heterogeneous stem cell pool and surrounding niche. Nat. Rev. Mol. Cell Biol. 14, 737–748 (2013).

    CAS  PubMed  Google Scholar 

  8. 8

    Arwert, E. N., Hoste, E. & Watt, F. M. Epithelial stem cells, wound healing and cancer. Nat. Rev. Cancer 12, 170–180 (2012).

    CAS  PubMed  Google Scholar 

  9. 9

    Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Donati, G. & Watt, F. M. Stem cell heterogeneity and plasticity in epithelia. Cell Stem Cell 16, 465–476 (2015).

    CAS  PubMed  Google Scholar 

  11. 11

    Blanpain, C. & Fuchs, E. Plasticity of epithelial stem cells in tissue regeneration. Science 344, 1242281 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Ito, M. 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).

    CAS  PubMed  Google Scholar 

  13. 13

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

    CAS  PubMed  Google Scholar 

  14. 14

    Mascré, G. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257–262 (2012).

    Google Scholar 

  15. 15

    Aragona, M. et al. Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat. Commun. 8, 14684 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Park, S. et al. Tissue-scale coordination of cellular behaviour promotes epidermal wound repair in live mice. Nat. Cell Biol. 19, 155–163 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

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

    CAS  PubMed  Google Scholar 

  18. 18

    Chou, W. C. et al. Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling. Nat. Med. 19, 924–929 (2013).

    CAS  PubMed  Google Scholar 

  19. 19

    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 

  20. 20

    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 

  21. 21

    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 

  22. 22

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    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 

  24. 24

    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 

  25. 25

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

    CAS  Google Scholar 

  26. 26

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

    CAS  Google Scholar 

  27. 27

    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 

  28. 28

    Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

    CAS  Google Scholar 

  29. 29

    Trumpp, A., Essers, M. & Wilson, A. Awakening dormant haematopoietic stem cells. Nat. Rev. Immunol. 10, 201–209 (2010).

    CAS  PubMed  Google Scholar 

  30. 30

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

    CAS  PubMed  Google Scholar 

  31. 31

    Lumière, A. & Bérard, L. Le Cancer, Maladie des Cicatrices. (Masson, 1929).

    Google Scholar 

  32. 32

    Schäfer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9, 628–638 (2008).

    Google Scholar 

  33. 33

    Dvorak, H. F. Tumors: wounds that do not heal — redux. Cancer Immunol. Res. 3, 1–11 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Youssef, K. K. et al. Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation. Nat. Cell Biol. 14, 1282–1294 (2012).

    CAS  Google Scholar 

  35. 35

    Wong, S. Y. & Reiter, J. F. Wounding mobilizes hair follicle stem cells to form tumors. Proc. Natl Acad. Sci. USA 108, 4093–4098 (2011).

    CAS  PubMed  Google Scholar 

  36. 36

    Wang, G. Y., Wang, J., Mancianti, M. L. & Epstein, E. H. Basal cell carcinomas arise from hair follicle stem cells in Ptch1+/− mice. Cancer Cell 19, 114–124 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Petersson, M. et al. Interfering with stem cell-specific gatekeeper functions controls tumour initiation and malignant progression of skin tumours. Nat. Commun. 6, 5874 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Kasper, M. et al. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc. Natl Acad. Sci. USA 108, 4099–4104 (2011).

    CAS  PubMed  Google Scholar 

  39. 39

    Sánchez-Danés, A. et al. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536, 298–303 (2016).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452, 650–653 (2008).

    CAS  PubMed  Google Scholar 

  41. 41

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

    CAS  PubMed  Google Scholar 

  42. 42

    Lapouge, G. et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl Acad. Sci. USA 108, 7431–7436 (2011).

    CAS  PubMed  Google Scholar 

  43. 43

    Li, S. et al. A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse. Mol. Carcinog. 52, 751–759 (2013).

    CAS  PubMed  Google Scholar 

  44. 44

    Page, M. E., Lombard, P., Ng, F., Göttgens, B. & Jensen, K. B. The epidermis comprises autonomous compartments maintained by distinct stem cell populations. Cell Stem Cell 13, 471–482 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Tan, S. & Barker, N. Epithelial stem cells and intestinal cancer. Semin. Cancer Biol. 32, 40–53 (2015).

    CAS  PubMed  Google Scholar 

  46. 46

    Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).

    CAS  Google Scholar 

  47. 47

    Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603–608 (2009).

    CAS  Google Scholar 

  48. 48

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

    CAS  Google Scholar 

  49. 49

    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. Dyn. 233, 1332–1336 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

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

    Google Scholar 

  51. 51

    Asfaha, S. et al. Krt19+/Lgr5 cells are radioresistant cancer-initiating stem cells in the colon and intestine. Cell Stem Cell 16, 627–638 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

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

    CAS  Google Scholar 

  53. 53

    Hartnett, L. & Egan, L. J. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis 33, 723–731 (2012).

    CAS  PubMed  Google Scholar 

  54. 54

    Davidson, L. A. et al. Targeted deletion of p53 in Lgr5-expressing intestinal stem cells promotes colon tumorigenesis in a preclinical model of colitis-associated cancer. Cancer Res. 75, 5392–5397 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Vitale, I., Manic, G., De Maria, R., Kroemer, G. & Galluzzi, L. DNA damage in stem cells. Mol. Cell 66, 306–319 (2017).

    CAS  PubMed  Google Scholar 

  56. 56

    Blanpain, C., Mohrin, M., Sotiropoulou, P. A. & Passegué, E. DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell 8, 16–29 (2011).

    CAS  PubMed  Google Scholar 

  57. 57

    Sotiropoulou, P. a et al. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat. Cell Biol. 12, 572–582 (2010).

    CAS  PubMed  Google Scholar 

  58. 58

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

    CAS  Google Scholar 

  59. 59

    Li, L. & Clevers, H. Coexistence of quiescent and active adult stem cells in mammals. Science 327, 542–545 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    White, A. C. et al. Stem cell quiescence acts as a tumour suppressor in squamous tumours. Nat. Cell Biol. 16, 99–107 (2014).

    CAS  PubMed  Google Scholar 

  61. 61

    Ansell, D. M., Kloepper, J. E., Thomason, H. A., Paus, R. & Hardman, M. J. Exploring the 'hair growth–wound healing connection': anagen phase promotes wound re-epithelialization. J. Invest. Dermatol. 131, 518–528 (2011).

    CAS  PubMed  Google Scholar 

  62. 62

    Liu, Y. et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 4, 37–48 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Seita, J., Rossi, D. J. & Weissman, I. L. Differential DNA damage response in stem and progenitor cells. Cell Stem Cell 7, 145–147 (2010).

    CAS  PubMed  Google Scholar 

  64. 64

    Sperka, T., Wang, J. & Rudolph, K. L. DNA damage checkpoints in stem cells, ageing and cancer. Nat. Rev. Mol. Cell Biol. 13, 579–590 (2012).

    CAS  PubMed  Google Scholar 

  65. 65

    Oliver, L. et al. Differentiation-related response to DNA breaks in human mesenchymal stem cells. Stem Cells 31, 800–807 (2013).

    CAS  PubMed  Google Scholar 

  66. 66

    Chang, C.-H. et al. Mammary stem cells and tumor-initiating cells are more resistant to apoptosis and exhibit increased DNA repair activity in response to DNA damage. Stem Cell Rep. 5, 378–391 (2015).

    CAS  Google Scholar 

  67. 67

    Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Wu, W. S. et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123, 641–653 (2005).

    CAS  PubMed  Google Scholar 

  69. 69

    Zilfou, J. T., Spector, M. S. & Lowe, S. W. Slugging it out: fine tuning the p53-PUMA death connection. Cell 123, 545–548 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Beerman, I., Seita, J., Inlay, M. A., Weissman, I. L. & Rossi, D. J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15, 37–50 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Moehrle, B. M. et al. Stem cell-specific mechanisms ensure genomic fidelity within HSCs and upon aging of HSCs. Cell Rep. 13, 2412–2424 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Rossi, D. J., Jamieson, C. H. M. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).

    CAS  PubMed  Google Scholar 

  73. 73

    Rossi, D. J. et al. Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle 6, 2371–2376 (2007).

    CAS  PubMed  Google Scholar 

  74. 74

    Hua, G. et al. Crypt base columnar stem cells in small intestines of mice are radioresistant. Gastroenterology 143, 1266–1276 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15, 19–33 (2014).

    CAS  Google Scholar 

  76. 76

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

    CAS  Google Scholar 

  77. 77

    Potten, C. S. Extreme sensitivity of some intestinal crypt cells to X and gamma irradiation. Nature 269, 518–521 (1977).

    CAS  PubMed  Google Scholar 

  78. 78

    Zhu, Y., Huang, Y. F., Kek, C. & Bulavin, D. V. Apoptosis differently affects lineage tracing of lgr5 and bmi1 intestinal stem cell populations. Cell Stem Cell 12, 298–303 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Ruzankina, Y. et al. Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1, 113–126 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Matsumura, H. et al. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 351, aad4395 (2016).

    PubMed  Google Scholar 

  81. 81

    Inomata, K. et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099 (2009).

    CAS  PubMed  Google Scholar 

  82. 82

    Sotiropoulou, P. a. et al. BRCA1 deficiency in skin epidermis leads to selective loss of hair follicle stem cells and their progeny. Genes Dev. 27, 39–51 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Nijnik, A. et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686–690 (2007).

    CAS  PubMed  Google Scholar 

  84. 84

    White, A. C. & Lowry, W. E. Refining the role for adult stem cells as cancer cells of origin. Trends Cell Biol. 25, 11–20 (2015).

    CAS  PubMed  Google Scholar 

  85. 85

    Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Saito, Y. et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat. Biotechnol. 28, 275–280 (2010).

    CAS  PubMed  Google Scholar 

  87. 87

    Slupianek, A. et al. Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G2/M phase, and protection from apoptosis. Mol. Cell. Biol. 22, 4189–4201 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Slupianek, A., Nowicki, M. O., Koptyra, M. & Skorski, T. BCR/ABL modifies the kinetics and fidelity of DNA double-strand breaks repair in hematopoietic cells. DNA Repair 5, 243–250 (2006).

    CAS  PubMed  Google Scholar 

  89. 89

    Nowicki, M. O. et al. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species — dependent DNA double-strand breaks. Am. Soc. Hematol. 104, 3746–3753 (2004).

    CAS  Google Scholar 

  90. 90

    Perrotti, D., Jamieson, C., Goldman, J. & Skorski, T. Chronic myeloid leukemia: mechanisms of blastic transformation. J. Clin. Invest. 120, 2254–2264 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Fuchs, Y. & Steller, H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat. Rev. Mol. Cell Biol. 16, 329–344 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Stenn, K. S., Lawrence, L., Veis, D., Korsmeyer, S. & Seiberg, M. Expression of the bcl-2 protooncogene in the cycling adult mouse hair follicle. J. Invest. Dermatol. 103, 107–111 (1994).

    CAS  PubMed  Google Scholar 

  94. 94

    Lindner, G. et al. Analysis of apoptosis during hair follicle regression (catagen). Am. J. Pathol. 151, 1601–1617 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Nishimura, E. K., Granter, S. R. & Fisher, D. E. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307, 720–724 (2005).

    CAS  PubMed  Google Scholar 

  96. 96

    Ito, M., Kizawa, K., Hamada, K. & Cotsarelis, G. 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).

    PubMed  Google Scholar 

  97. 97

    Merritt, A. J. et al. Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. J. Cell Sci. 108, 2261–2271 (1995).

    CAS  PubMed  Google Scholar 

  98. 98

    van der Heijden, M. et al. Bcl-2 is a critical mediator of intestinal transformation. Nat. Commun. 7, 10916 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Flohil, C. C., Janssen, P. A. & Bosman, F. T. Expression of Bcl-2 protein in hyperplastic polyps, adenomas, and carcinomas of the colon. J. Pathol. 178, 393–397 (1996).

    CAS  PubMed  Google Scholar 

  100. 100

    Motoyama, N. et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267, 1506–1510 (1995).

    CAS  PubMed  Google Scholar 

  101. 101

    Lagadinou, E. D. et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12, 329–341 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Delia, D. et al. bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells. Blood 79, 1291–1298 (1992).

    CAS  PubMed  Google Scholar 

  103. 103

    Campbell, C. J. V. et al. The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity. Blood 116, 1433–1442 (2010).

    CAS  PubMed  Google Scholar 

  104. 104

    Domen, J. & Weissman, I. L. Hematopoietic stem cells and other hematopoietic cells show broad resistance to chemotherapeutic agents in vivo when overexpressing bcl-2. Exp. Hematol. 31, 631–639 (2003).

    CAS  PubMed  Google Scholar 

  105. 105

    Goff, D. J. et al. A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition. Cell Stem Cell 12, 316–328 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Campbell, K. J. et al. Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance. Blood 116, 3197–3207 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Larisch, S. et al. A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat. Cell Biol. 2, 915–921 (2000).

    CAS  PubMed  Google Scholar 

  108. 108

    Elhasid, R. et al. Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic leukemia patients. Oncogene 23, 5468–5475 (2004).

    CAS  PubMed  Google Scholar 

  109. 109

    Garcia-Fernandez, M. et al. Sept4/ARTS is required forstem cell apoptosis and tumor suppression. Genes Dev. 24, 2282–2293 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Fuchs, Y. et al. Sept4/ARTS Regulates Stem Cell Apoptosis and Skin Regeneration. Science 341, 286–289 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Fogarty, C. E. & Bergmann, A. The sound of silence: signaling by apoptotic cells. Curr. Top. Dev. Biol. 114, 241–265 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Pérez-Garijo, A. & Steller, H. Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease. Development 142, 3253–3262 (2015).

    PubMed  PubMed Central  Google Scholar 

  113. 113

    Chera, S. et al. Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. Dev. Cell 17, 279–289 (2009).

    CAS  PubMed  Google Scholar 

  114. 114

    Hay, B. a, Wolff, T. & Rubin, G. M. Expression of baculovirus P35 prevents cell death in Drosophila. Development 120, 2121–2129 (1994).

    CAS  PubMed  Google Scholar 

  115. 115

    Ryoo, H. D., Gorenc, T. & Steller, H. Apoptotic cells can induce compensatory cell proliferation through the JNK and the wingless signaling pathways. Dev. Cell 7, 491–501 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Pérez-Garijo, A., Martín, F. a & Morata, G. Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila. Development 131, 5591–5598 (2004).

    PubMed  Google Scholar 

  117. 117

    Huh, J. R., Guo, M. & Hay, B. A. Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase dronc in a nonapoptotic role. Curr. Biol. 14, 1262–1266 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Pérez-Garijo, A., Shlevkov, E. & Morata, G. The role of Dpp and Wg in compensatory proliferation and in the formation of hyperplastic overgrowths caused by apoptotic cells in the Drosophila wing disc. Development 136, 1169–1177 (2009).

    PubMed  Google Scholar 

  119. 119

    Fan, Y. et al. Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila. PLoS Genet. 10, e1004131 (2014).

    PubMed  PubMed Central  Google Scholar 

  120. 120

    Kondo, S., Senoo-Matsuda, N., Hiromi, Y. & Miura, M. DRONC coordinates cell death and compensatory proliferation. Mol. Cell. Biol. 26, 7258–7268 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Fan, Y. & Bergmann, A. Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye. Dev. Cell 14, 399–410 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Fogarty, C. E. et al. Extracellular reactive oxygen species drive apoptosis-induced proliferation via Drosophila macrophages. Curr. Biol. 26, 575–584 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Jiang, H. et al. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137, 1343–1355 (2009).

    PubMed  PubMed Central  Google Scholar 

  124. 124

    Patel, P. H., Dutta, D. & Edgar, B. A. Niche appropriation by Drosophila intestinal stem cell tumours. Nat. Cell Biol. 17, 1182–1192 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Bilak, A., Uyetake, L. & Su, T. T. Dying cells protect survivors from radiation-induced cell death in Drosophila. PLoS Genet. 10, e1004220 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. 126

    Li, F. et al. Apoptotic cells activate the 'phoenix rising' pathway to promote wound healing and tissue regeneration. Sci. Signal. 3, ra13 (2010).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Goessling, W. et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell 136, 1136–1147 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Lauber, K. et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717–730 (2003).

    CAS  PubMed  Google Scholar 

  129. 129

    Thomson, J. A., Shapiro, S. S., Waknitz, M. A. & Marshall, V. S. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  Google Scholar 

  130. 130

    Trempus, C. S. et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J. Invest. Dermatol. 120, 501–511 (2003).

    CAS  PubMed  Google Scholar 

  131. 131

    Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    CAS  Google Scholar 

  132. 132

    Soteriou, D. et al. Comparative proteomic analysis of supportive and unsupportive extracellular matrix substrates for human embryonic stem cell maintenance. J. Biol. Chem. 288, 18716–18731 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860–866 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Donato, A. L. et al. Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy. J. Invest. Dermatol. 134, 1686–1692 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Liu, X. et al. Caspase-3 promotes genetic instability and carcinogenesis. Mol. Cell 58, 284–296 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Ichim, G. et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 57, 860–872 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Tang, H. L. et al. Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol. Biol. Cell 23, 2240–2252 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Cartwright, I. M., Liu, X., Zhou, M., Li, F. & Li, C.-Y. Essential roles of Caspase-3 in facilitating Myc-induced genetic instability and carcinogenesis. eLife 6, e26371 (2017).

    PubMed  PubMed Central  Google Scholar 

  139. 139

    Pérez, E., Lindblad, J. L. & Bergmann, A. Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila. eLife 6, e26747 (2017).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Ichim, G. & Tait, S. W. G. A fate worse than death: apoptosis as an oncogenic process. Nat. Rev. Cancer 16, 539–548 (2016).

    CAS  Google Scholar 

  141. 141

    Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755–768 (2008).

    CAS  PubMed  Google Scholar 

  142. 142

    Kurtova, A. V. et al. Blocking PGE2-induced tumour repopulaiton abrogates bladder cancer chemoresistance. Nature 517, 209–213 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. 143

    Chammas, R., de Sousa Andrade, L. N. & Jancar, S. Oncogenic effects of PAFR ligands produced in tumours upon chemotherapy and radiotherapy. Nat. Rev. Cancer 17, 253–253 (2017).

    CAS  PubMed  Google Scholar 

  144. 144

    Mao, P., Smith, L., Xie, W. & Wang, M. Dying endothelial cells stimulate proliferation of malignant glioma cells via a caspase 3-mediated pathway. Oncol. Lett. 5, 1615–1620 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Morata, G. & Martín, F. A. Cell competition: the embrace of death. Dev. Cell 13, 1–2 (2007).

    CAS  PubMed  Google Scholar 

  146. 146

    Moreno, E. Is cell competition relevant to cancer? Nat. Rev. Cancer 8, 141–147 (2008).

    CAS  Google Scholar 

  147. 147

    Suijkerbuijk, S. J. E., Kolahgar, G., Kucinski, I. & Piddini, E. Cell competition drives the growth of intestinal adenomas in Drosophila. Curr. Biol. 26, 428–438 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Eichenlaub, T., Cohen, S. M. & Herranz, H. Cell competition drives the formation of metastatic tumors in a drosophila model of epithelial tumor formation. Curr. Biol. 26, 419–427 (2016).

    CAS  PubMed  Google Scholar 

  149. 149

    Ballesteros-Arias, L., Saavedra, V. & Morata, G. Cell competition may function either as tumour-suppressing or as tumour-stimulating factor in Drosophila. Oncogene 33, 4377–4384 (2014).

    CAS  PubMed  Google Scholar 

  150. 150

    Kolahgar, G. et al. Cell competition modifies adult stem cell and tissue population dynamics in a JAK-STAT-dependent manner. Dev. Cell 34, 297–309 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Bondar, T. & Medzhitov, R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6, 309–322 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Dumble, M. et al. The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood 109, 1736–1742 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Stine, R. R. & Matunis, E. L. Stem cell competition: finding balance in the niche. Trends Cell Biol. 23, 357–364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Sancho, M. et al. Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation. Dev. Cell 26, 19–30 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Clavería, C., Giovinazzo, G., Sierra, R. & Torres, M. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500, 39–44 (2013).

    PubMed  Google Scholar 

  156. 156

    Brown, S. et al. Correction of aberrant growth preserves tissue homeostasis. Nature 548, 334–337 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Pérez-Garijo, A., Fuchs, Y. & Steller, H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. eLife 2, e01004 (2013).

    PubMed  PubMed Central  Google Scholar 

  158. 158

    Prise, K. M. & O'Sullivan, J. M. Radiation-induced bystander signalling in cancer therapy. Nat. Rev. Cancer 9, 351–360 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Gauron, C. et al. Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed. Sci. Rep. 3, 2084 (2013).

    PubMed  PubMed Central  Google Scholar 

  160. 160

    Nguyen-Chi, M. et al. TNF signaling and macrophages govern fin regeneration in zebrafish larvae. Cell Death Dis. 8, e2979 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Bhola, P. D. & Letai, A. Mitochondria-judges and executioners of cell death sentences. Mol. Cell 61, 695–704 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Delbridge, A. R. D., Grabow, S., Strasser, A. & Vaux, D. L. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer 16, 99–109 (2016).

    CAS  Google Scholar 

  163. 163

    Fulda, S. & Vucic, D. Targeting IAP proteins for therapeutic intervention in cancer. Nat. Rev. Drug Discov. 11, 109–124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Ashkenazi, A., Fairbrother, W. J., Leverson, J. D. & Souers, A. J. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat. Rev. Drug Discov. 16, 273–284 (2017).

    CAS  PubMed  Google Scholar 

  165. 165

    Chonghaile, T. N. et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129–1133 (2011).

    CAS  PubMed Central  Google Scholar 

  166. 166

    Sarosiek, K. A. et al. Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell 31, 142–156 (2017).

    CAS  PubMed  Google Scholar 

  167. 167

    Certo, M. et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9, 351–365 (2006).

    CAS  Google Scholar 

  168. 168

    Vo, T. T. et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell 151, 344–355 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Koren, E. & Fuchs, Y. The bad seed: cancer stem cells in tumor development and resistance. Drug Resist. Updat. 28, 1–12 (2016).

    PubMed  Google Scholar 

  170. 170

    Carter, B. Z. et al. Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci. Transl Med. 8, 355ra117 (2016).

    PubMed  PubMed Central  Google Scholar 

  171. 171

    Carter, B. Z. et al. Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. J. Natl. Cancer Inst. 106, djt440 (2014).

    PubMed  PubMed Central  Google Scholar 

  172. 172

    Carter, B. Z. et al. XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34+38- cells in a phase 1/2 study of patients with relapsed/refractory AML. Apoptosis 16, 67–74 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Pérez-Mancera, P. A., Young, A. R. J. & Narita, M. Inside and out: the activities of senescence in cancer. Nat. Rev. Cancer 14, 547–558 (2014).

    PubMed  Google Scholar 

  174. 174

    Muñoz-Espín, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).

    PubMed  Google Scholar 

  175. 175

    Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).

    CAS  Google Scholar 

  176. 176

    Campisi, J. & d'Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007).

    CAS  PubMed  Google Scholar 

  177. 177

    de Keizer, P. L. J. The fountain of youth by targeting senescent cells? Trends Mol. Med. 23, 6–17 (2017).

    PubMed  Google Scholar 

  178. 178

    Serrano, M. Senescence helps regeneration. Dev. Cell 31, 671–672 (2014).

    CAS  PubMed  Google Scholar 

  179. 179

    Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181

    Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, aaf4445 (2016).

    PubMed  Google Scholar 

  182. 182

    Chiche, A. et al. Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell Stem Cell 20, 407–414 (2017).

    CAS  PubMed  Google Scholar 

  183. 183

    Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.-Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    CAS  Google Scholar 

  184. 184

    Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    CAS  Google Scholar 

  185. 185

    Merritt, A. J. et al. The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res. 54, 614–617 (1994).

    CAS  PubMed  Google Scholar 

  186. 186

    Chang, H. H. Y., Pannunzio, N. R., Adachi, N. & Lieber, M. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol. 18, 495–506 (2017).

    CAS  PubMed  Google Scholar 

  187. 187

    Panier, S. & Boulton, S. J. Double-strand break repair: 53BP1 comes into focus. Nat. Rev. Mol. Cell Biol. 15, 7–18 (2013).

    PubMed  Google Scholar 

  188. 188

    Tait, S. W. G. & Green, D. R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11, 621–632 (2010).

    CAS  Google Scholar 

  189. 189

    Salvesen, G. S. & Walsh, C. M. Functions of caspase 8: the identified and the mysterious. Semin. Immunol. 26, 246–252 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).

    CAS  Google Scholar 

  191. 191

    Liu, J. C., Lerou, P. H. & Lahav, G. Stem cells: balancing resistance and sensitivity to DNA damage. Trends Cell Biol. 24, 268–274 (2014).

    PubMed  PubMed Central  Google Scholar 

  192. 192

    Martinou, J. C. & Youle, R. J. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev. Cell 21, 92–101 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Salvesen, G. S. & Duckett, C. S. IAP proteins: blocking the road to death's door. Nat. Rev. Mol. Cell Biol. 3, 401–410 (2002).

    CAS  PubMed  Google Scholar 

  194. 194

    Bratton, S. B. & Salvesen, G. S. Regulation of the Apaf-1-caspase-9 apoptosome. J. Cell Sci. 123, 3209–3214 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors apologize to colleagues whose contributions could not be adequately cited because of space constraints. The authors thank E. Koren, I. Maniv, Y. Yosefzon and A. Pérez-Garijo for discussion, advice and assistance. D.S. is supported by the Aly-Kaufman and Coleman-Cohen fellowship. Y.F. is the Deloro Career Advancement Chair and is supported by the German-Israeli Foundation for Scientific Research and Development (GIF; I-2381-412.13/2015) and Israel Cancer Research Fund (ICRF; 15-771-RCDA) grants.

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Both authors researched data for the article; made substantial contributions to discussing the content; and wrote, reviewed and edited the manuscript.

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Correspondence to Yaron Fuchs.

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Glossary

Adult stem cells

(SCs). Stem cells found in different tissues in the adult organism that divide to replenish tissues and organs.

Alopecia

Loss of hair from parts of the head or body.

BH3 mimetics

A class of small-molecule compounds that mimic the action of proapoptotic BH3-only proteins by binding the prosurvival BCL-2 family members and consequently activating apoptosis in cells that express these proteins.

BH3 profiling

A tool used to predict the cellular response to different synthetic BH3 peptides that mimic BH3-only proteins. It provides information on which BCL-2 family protein is required for survival of specific cell types (healthy or malignant).

Blastema

A transient structure formed during regeneration that consists of a proliferating mass of a morphologically homogeneous population of undifferentiated cells.

Cancer stem cell

(CSC). An immortal cell that resides within the tumour and is equipped with the capacity to self-renew and differentiate into different cell types that make up the tumour.

Caspases

A family of cysteine proteases that cleave various substrates in the cell to implement apoptosis.

Homologous recombination

(HR). A DNA double strand break repair mechanism in which the genomic sequence of the broken DNA ends is restored by using sister chromatids as a template for the repair.

Interfollicular epidermis

(IFE). A stratified squamous epithelium consisting of a basal layer of proliferative cells that differentiate while they migrate upwards to form the outermost layers of the skin.

Keratin pearls

A keratinized structure formed by concentric layers of malignant squamous cells that reside in the centre of most squamous cell carcinomas.

Lineage tracing

The process of identifying all progeny of a single cell.

Nonhomologous end joining

(NHEJ). A DNA double strand break repair mechanism in which damaged DNA is repaired by bringing together the two broken ends and rejoining them by DNA ligation, resulting in small loss of nucleotides.

Progenitor cells

Dividing cells with the capacity to differentiate into a restricted lineage.

Quiescent

A reversible state of cell cycle arrest where cells cease to proliferate but retain their ability to re-enter the cell cycle upon specific signals.

Self-renewal

The process by which stem cells generate additional stem cells to maintain the stem cell pool.

Senescence

An irreversible state of cell cycle arrest characterized by sustained metabolic activity, changes in morphology and unresponsiveness to growth factors.

Stem cell niches

The microenvironments where stem cells reside, which maintain and regulate their fate.

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Soteriou, D., Fuchs, Y. A matter of life and death: stem cell survival in tissue regeneration and tumour formation. Nat Rev Cancer 18, 187–201 (2018). https://doi.org/10.1038/nrc.2017.122

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