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Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style

Key Points

  • Mature, terminally differentiated cells have the capacity to de-differentiate or transdifferentiate in vivo.

  • De-differentiation and transdifferentiation can be forced experimentally, but these processes also occur physiologically in response to tissue injury and/or cell loss.

  • Cellular plasticity involves the repression of genes associated with the previous cell type, as well as activation of genes associated with the new cell type.

  • Cells may occupy 'intermediate' identity states while undergoing de-differentiation or transdifferentiation. Such changes can be reversible.

  • Cellular plasticity can be driven by factors that induce a new identity or by the loss of inhibitory factors that maintain the old identity.

Abstract

Biologists have long been intrigued by the possibility that cells can change their identity, a phenomenon known as cellular plasticity. The discovery that terminally differentiated cells can be experimentally coaxed to become pluripotent has invigorated the field, and recent studies have demonstrated that changes in cell identity are not limited to the laboratory. Specifically, certain adult cells retain the capacity to de-differentiate or transdifferentiate under physiological conditions, as part of an organ's normal injury response. Recent studies have highlighted the extent to which cell plasticity contributes to tissue homeostasis, findings that have implications for cell-based therapy.

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Figure 1: Models of differentiation, de-differentiation and transdifferentiation.
Figure 2: Examples of de-differentiation.
Figure 3: Signalling from surrounding cells and the environment induces de-differentiation.
Figure 4: Transdifferentiation in the liver and pancreas leads to tissue repair.

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References

  1. Holliday, R. Epigenetics: a historical overview. Epigenetics 1, 76–80 (2006).

    Article  PubMed  Google Scholar 

  2. Del Rio-Tsonis, K. & Tsonis, P. A. Eye regeneration at the molecular age. Dev. Dyn. 226, 211–224 (2003).

    Article  PubMed  Google Scholar 

  3. Gurdon, J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).

    CAS  PubMed  Google Scholar 

  4. Worley, M. I., Setiawan, L. & Hariharan, I. K. Regeneration and transdetermination in Drosophila imaginal discs. Annu. Rev. Genet. 46, 289–310 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Raff, M. Adult stem cell plasticity: fact or artifact? Annu. Rev. Cell Dev. Biol. 19, 1–22 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Jopling, C., Boue, S. & Izpisua Belmonte, J. C. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat. Rev. Mol. Cell Biol. 12, 79–89 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Tapscott, S. J. et al. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science 242, 405–411 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).

    Article  CAS  PubMed  Google Scholar 

  10. Galliot, B. Hydra, a fruitful model system for 270 years. Int. J. Dev. Biol. 56, 411–423 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Baguna, J. The planarian neoblast: the rambling history of its origin and some current black boxes. Int. J. Dev. Biol. 56, 19–37 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Morgan, T. H. Growth and regeneration in Planaria lugubris. Arch. Ent. Mech. Org. 13, 179–212 (1902).

    Google Scholar 

  13. Goss, R. J. Kinetics of compensatory growth. Q. Rev. Biol. 40, 123–146 (1965).

    Article  CAS  PubMed  Google Scholar 

  14. de Cuevas, M. & Matunis, E. L. The stem cell niche: lessons from the Drosophila testis. Development 138, 2861–2869 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tulina, N. & Matunis, E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science 294, 2546–2549 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B. & Fuller, M. T. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 294, 2542–2545 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Brawley, C. & Matunis, E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304, 1331–1334 (2004). This paper demonstrates that differentiated spermatogonia can de-differentiate into germline stem cells in D. melanogaster mutants after extreme germline stem cell loss.

    Article  CAS  PubMed  Google Scholar 

  18. Sheng, X. R., Brawley, C. M. & Matunis, E. L. Dedifferentiating spermatogonia outcompete somatic stem cells for niche occupancy in the Drosophila testis. Cell Stem Cell 5, 191–203 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Barroca, V. et al. Mouse differentiating spermatogonia can generate germinal stem cells in vivo. Nat. Cell Biol. 11, 190–196 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Nakagawa, T., Sharma, M., Nabeshima, Y., Braun, R. E. & Yoshida, S. Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science 328, 62–67 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004). This study shows that differentiating cyst cells in the D. melanogaster ovary can de-differentiate into germline stem cells when the germline stem cells are lost to excessive differentiation.

    Article  CAS  PubMed  Google Scholar 

  22. Steen, T. P. Stability of chondrocyte differentiation and contribution of muscle to cartilage during limb regeneration in the axolotl (Siredon mexicanum). J. Exp. Zool. 167, 49–78 (1968).

    Article  CAS  PubMed  Google Scholar 

  23. Tanaka, E. M. & Reddien, P. W. The cellular basis for animal regeneration. Dev. Cell 21, 172–185 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kragl, M. et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460, 60–65 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Sandoval-Guzman, T. et al. Fundamental differences in dedifferentiation and stem cell recruitment during skeletal muscle regeneration in two salamander species. Cell Stem Cell 14, 174–187 (2014). Sandoval-Guzman et al . find that after limb amputation, certain species of salamanders use de-differentiation of post-mitotic muscle fibres to produce more muscle progenitors for limb regeneration.

    Article  CAS  PubMed  Google Scholar 

  26. Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Kikuchi, K. et al. Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature 464, 601–605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jopling, C. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Goodell, M. A., Nguyen, H. & Shroyer, N. Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. Nat. Rev. Mol. Cell Biol. 16, 299–309 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Greco, V. et al. A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell 4, 155–169 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hsu, Y. C., Pasolli, H. A. & Fuchs, E. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell 144, 92–105 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rompolas, P., Mesa, K. R. & Greco, V. Spatial organization within a niche as a determinant of stem-cell fate. Nature 502, 513–518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fullgrabe, A. et al. Dynamics of Lgr6 progenitor cells in the hair follicle, sebaceous gland, and interfollicular epidermis. Stem Cell Rep. 5, 843–855 (2015).

    Article  CAS  Google Scholar 

  36. Seifert, A. W. et al. Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature 489, 561–565 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat. Cell Biol. 14, 1099–1104 (2012). This study finds that committed secretory precursors de-differentiate into new crypt stem cells following intestinal crypt injury, and that these de-differentiated stem cells can ultimately produce all of the cell types of the intestine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Stange, D. E. et al. Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell 155, 357–368 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Evans, M. J., Van Winkle, L. S., Fanucchi, M. V. & Plopper, C. G. Cellular and molecular characteristics of basal cells in airway epithelium. Exp. Lung Res. 27, 401–415 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Schoch, K. G. et al. A subset of mouse tracheal epithelial basal cells generates large colonies in vitro. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L631–L642 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Rock, J. R. et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106, 12771–12775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hong, K. U., Reynolds, S. D., Watkins, S., Fuchs, E. & Stripp, B. R. In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L643–L649 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Tata, P. R. et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503, 218–223 (2013). This study demonstrates that differentiated cells are able to de-differentiate in response to stem cell ablation to replenish the stem cell population, and that this de-differentiation is likely to be inhibited and regulated by contact with existing stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mirsky, R. et al. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J. Peripher. Nerv. Syst. 13, 122–135 (2008).

    Article  PubMed  Google Scholar 

  48. Painter, M. W. et al. Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration. Neuron 83, 331–343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang, H. et al. Turning terminally differentiated skeletal muscle cells into regenerative progenitors. Nat. Commun. 6, 7916 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pajcini, K. V., Corbel, S. Y., Sage, J., Pomerantz, J. H. & Blau, H. M. Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell 7, 198–213 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. de Lau, W., Peng, W. C., Gros, P. & Clevers, H. The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 28, 305–316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Monje, P. V., Soto, J., Bacallao, K. & Wood, P. M. Schwann cell dedifferentiation is independent of mitogenic signaling and uncoupled to proliferation: role of cAMP and JNK in the maintenance of the differentiated state. J. Biol. Chem. 285, 31024–31036 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhao, R. et al. Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev. Cell 30, 151–165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wagers, A. J. & Weissman, I. L. Plasticity of adult stem cells. Cell 116, 639–648 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Huang, P. et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386–389 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Khurana, S. & Mukhopadhyay, A. In vitro transdifferentiation of adult hematopoietic stem cells: an alternative source of engraftable hepatocytes. J. Hepatol. 49, 998–1007 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Riddle, M. R., Weintraub, A., Nguyen, K. C., Hall, D. H. & Rothman, J. H. Transdifferentiation and remodeling of post-embryonic C. elegans cells by a single transcription factor. Development 140, 4844–4849 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jarriault, S., Schwab, Y. & Greenwald, I. A. Caenorhabditis elegans model for epithelial-neuronal transdifferentiation. Proc. Natl Acad. Sci. USA 105, 3790–3795 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Freedman, B. D. et al. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev. Cell 26, 666–673 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Maki, N. et al. Expression of stem cell pluripotency factors during regeneration in newts. Dev. Dyn. 238, 1613–1616 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Maki, N. et al. Oocyte-type linker histone B4 is required for transdifferentiation of somatic cells in vivo. FASEB J. 24, 3462–3467 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mizuno, N., Agata, K., Sawada, K., Mochii, M. & Eguchi, G. Expression of crystallin genes in embryonic and regenerating newt lenses. Dev. Growth Differ. 44, 251–256 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Reyer, R. W., Woolfitt, R. A. & Withersty, L. T. Stimulation of lens regeneration from the newt dorsal iris when implanted into the blastema of the regenerating limb. Dev. Biol. 32, 258–281 (1973).

    Article  CAS  PubMed  Google Scholar 

  65. Ito, M., Hayashi, T., Kuroiwa, A. & Okamoto, M. Lens formation by pigmented epithelial cell reaggregate from dorsal iris implanted into limb blastema in the adult newt. Dev. Growth Differ. 41, 429–440 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Song, K. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Qian, L. et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485, 593–598 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. & Melton, D. A. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455, 627–632 (2008). This study finds that forced expression of β-cell-specific transcription factors in pancreatic acinar cells leads to transdifferentiation of acinar cells directly into functional β-cells.

    Article  CAS  PubMed  Google Scholar 

  70. Stanger, B. Z. Cellular homeostasis and repair in the mammalian liver. Annu. Rev. Physiol. 77, 179–200 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yanger, K. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 27, 719–724 (2013). Using genetic lineage tracing, Yanger et al . find that forced NOTCH signalling or injury is sufficient to induce hepatocytes to transdifferentiate into biliary cells in a stepwise process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tarlow, B. D. et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15, 605–618 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Michalopoulos, G. K., Barua, L. & Bowen, W. C. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41, 535–544 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Koh, D. S., Cho, J. H. & Chen, L. Paracrine interactions within islets of Langerhans. J. Mol. Neurosci. 48, 429–440 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Cogger, K. & Nostro, M. C. Recent advances in cell replacement therapies for the treatment of type 1 diabetes. Endocrinology 156, 8–15 (2015).

    Article  PubMed  Google Scholar 

  76. Kushner, J. A., MacDonald, P. E. & Atkinson, M. A. Stem cells to insulin secreting cells: two steps forward and now a time to pause? Cell Stem Cell 15, 535–536 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Baeyens, L. et al. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat. Biotechnol. 32, 76–83 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, Y. J. et al. De novo formation of insulin-producing “neo-β cell islets” from intestinal crypts. Cell Rep. 6, 1046–1058 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ferber, S. et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat. Med. 6, 568–572 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Shternhall-Ron, K. et al. Ectopic PDX-1 expression in liver ameliorates type 1 diabetes. J. Autoimmun. 28, 134–142 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Horb, M. E., Shen, C. N., Tosh, D. & Slack, J. M. Experimental conversion of liver to pancreas. Curr. Biol. 13, 105–115 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Thorel, F. et al. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464, 1149–1154 (2010). Thorel et al . determine that following β-cell ablation in the pancreas, α-cells can transdifferentiate into functional β-cells without needing exogenous factors to initiate transdifferentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chera, S. et al. Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature 514, 503–507 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gao, T. et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab. 19, 259–271 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dhawan, S., Georgia, S., Tschen, S. I., Fan, G. & Bhushan, A. Pancreatic β cell identity is maintained by DNA methylation-mediated repression of Arx. Dev. Cell 20, 419–429 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150, 1223–1234 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Guo, S. et al. Inactivation of specific β cell transcription factors in type 2 diabetes. J. Clin. Invest. 123, 3305–3316 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zuryn, S. et al. Sequential histone-modifying activities determine the robustness of transdifferentiation. Science 345, 826–829 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Zong, Y. et al. Notch signaling controls liver development by regulating biliary differentiation. Development 136, 1727–1739 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yanger, K. & Stanger, B. Z. Liver cell reprogramming: parallels with iPSC biology. Cell Cycle 13, 1211–1212 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Katsuyama, T. & Paro, R. Epigenetic reprogramming during tissue regeneration. FEBS Lett. 585, 1617–1624 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Slack, J. M. Metaplasia and transdifferentiation: from pure biology to the clinic. Nat. Rev. Mol. Cell Biol. 8, 369–378 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Tosh, D. & Slack, J. M. How cells change their phenotype. Nat. Rev. Mol. Cell Biol. 3, 187–194 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Corbett, J. L. & Tosh, D. Conversion of one cell type into another: implications for understanding organ development, pathogenesis of cancer and generating cells for therapy. Biochem. Soc. Trans. 42, 609–616 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Shaheen, N. J. & Richter, J. E. Barrett's oesophagus. Lancet 373, 850–861 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Bhat, S. et al. Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study. J. Natl Cancer Inst. 103, 1049–1057 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Hvid-Jensen, F., Pedersen, L., Drewes, A. M., Sorensen, H. T. & Funch-Jensen, P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N. Engl. J. Med. 365, 1375–1383 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Stanger, B. Z. & Hebrok, M. Control of cell identity in pancreas development and regeneration. Gastroenterology 144, 1170–1179 (2013).

    Article  PubMed  Google Scholar 

  101. Grippo, P. J., Nowlin, P. S., Demeure, M. J., Longnecker, D. S. & Sandgren, E. P. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res. 63, 2016–2019 (2003).

    CAS  PubMed  Google Scholar 

  102. De La, O. J. et al. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc. Natl Acad. Sci. USA 105, 18907–18912 (2008).

    Article  Google Scholar 

  103. Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012). This study shows that acinar-to-ductal metaplasia and expression of ductal genes are crucial for inducing acinar cells to give rise to pancreatic ductal adenocarcinoma, and suggests that cellular reprogramming may be a crucial step in tumour initiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhu, L., Shi, G., Schmidt, C. M., Hruban, R. H. & Konieczny, S. F. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am. J. Pathol. 171, 263–273 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Krah, N. M. et al. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. eLife 4, e07125 (2015).

    Article  PubMed Central  Google Scholar 

  106. Fan, B. et al. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Invest. 122, 2911–2915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sekiya, S. & Suzuki, A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J. Clin. Invest. 122, 3914–3918 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Villanueva, A. et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143, 1660–1669.e7 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Li, H. et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int. 32, 38–47 (2012).

    Article  PubMed  CAS  Google Scholar 

  110. Abollo-Jimenez, F., Jimenez, R. & Cobaleda, C. Physiological cellular reprogramming and cancer. Semin. Cancer Biol. 20, 98–106 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Bjornson, C. R., Rietze, R. L., Reynolds, B. A., Magli, M. C. & Vescovi, A. L. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283, 534–537 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Petersen, B. E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Carriere, C., Seeley, E. S., Goetze, T., Longnecker, D. S. & Korc, M. The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia. Proc. Natl Acad. Sci. USA 104, 4437–4442 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Khan, M. S., Thornhill, J. A., Gaffney, E., Loftus, B. & Butler, M. R. Keratinising squamous metaplasia of the bladder: natural history and rationalization of management based on review of 54 years experience. Eur. Urol. 42, 469–474 (2002).

    Article  PubMed  Google Scholar 

  115. de Vries, A. C. & Kuipers, E. J. Epidemiology of premalignant gastric lesions: implications for the development of screening and surveillance strategies. Helicobacter 12 (Suppl. 2), 22–31 (2007).

    Article  PubMed  Google Scholar 

  116. Elson, D. A. et al. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. Cancer Res. 60, 1267–1275 (2000).

    CAS  PubMed  Google Scholar 

  117. Daniels, J. M. & Sutedja, T. G. Detection and minimally invasive treatment of early squamous lung cancer. Ther. Adv. Med. Oncol. 5, 235–248 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Defourny, J. et al. Cochlear supporting cell transdifferentiation and integration into hair cell layers by inhibition of ephrin-B2 signalling. Nat. Commun. 6, 7017 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. Jain, R. et al. Plasticity of Hopx+ type I alveolar cells to regenerate type II cells in the lung. Nat. Commun. 6, 6727 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Pfisterer, U. et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl Acad. Sci. USA 108, 10343–10348 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nakagawa, N. & Duffield, J. S. Myofibroblasts in fibrotic kidneys. Curr. Pathobiol. Rep. 1, 189–198 (2013).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are indebted to Pantelis Rompolas for helpful comments on the manuscript. A.M. is supported by a grant from the Cholangiocarcinoma Foundation. B.Z.S. is supported by grants from the US National Institutes of Health (NIH; DK104196 and CA169123), the Penn Institute for Regenerative Medicine, the Biesecker Pediatric Liver Center and the Abramson Family Cancer Research Institute.

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Correspondence to Ben Z. Stanger.

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Glossary

Progenitor cell

An immature cell, often lineage-restricted, that can proliferate and give rise to differentiated cells. This is often a short-term state compared to stem cell populations, which may be maintained for a lifetime. Progenitor cells are also sometimes referred to as transit-amplifying cells.

Reprogramming

A change in the identity of a differentiated cell. Usage of this term often overlaps with de- and transdifferentiation, although reprogramming generally refers to a complete and stable shift. The most extreme example is reprogramming of a differentiated cell to a pluripotent state.

Epimorphosis

Morgan's term for regeneration using cellular proliferation.

Morphyllaxis

Morgan's term for regeneration using existing material in the animal, without relying on proliferation.

Lineage tracing

Tracing the progeny and fate of a population of cells using permanent labelling.

Schwann cells

Cells that surround and envelope neurons in myelin sheaths, allowing for proper conduction along the nerve.

Lateral plate mesoderm

A developmental division of mesoderm that gives rise to tendon, bone, connective tissue and dermis within the vertebrate limb.

Multinucleated myofibres

Syncytial muscle fibres formed from many muscle progenitors that fuse together to generate a single fibre with many nuclei.

Satellite cells

PAX7+ muscle stem cells that reside next to muscle fibres and mediate muscle regeneration in many vertebrate species.

Sarcomere apparatus

Actin, myosin and associated proteins within mature muscle fibres that are organized in such a way that they can move relative to each other to produce muscle contractions.

Myelin

An electrically insulating sheath provided by Schwann cell membranes that surrounds axons.

Linker histone

A histone that is responsible for stabilizing the complex of DNA wrapped around histones that forms nucleosomes.

Somatic cell nuclear transfer

(SCNT). A technique whereby nuclei from differentiated cells are transplanted into oocytes. These nuclei are reprogrammed to a pluripotent state and can, ultimately, generate a new organism.

Pluripotency factors

The OCT3/4, SOX2, KLF4 and MYC (OSKM) transcription factors that can induce differentiated cells to reprogramme into induced pluripotent stem cells. Also known as Yamanaka factors.

Pancreatic islets of Langerhans

Endocrine cells in the pancreas that are responsible for producing the hormones used for glucose management.

Glucagon

A hormone secreted by pancreatic α-cells that increases serum glucose levels.

Somatostatin

A hormone secreted by pancreatic δ-cells that inhibits the secretion of other pancreatic hormones.

Metaplasia

Changes in tissue whereby one cell type is replaced by another, often associated with increased cancer risk.

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Merrell, A., Stanger, B. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol 17, 413–425 (2016). https://doi.org/10.1038/nrm.2016.24

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