Review Article | Published:

Diverse mechanisms for endogenous regeneration and repair in mammalian organs

Naturevolume 557pages322328 (2018) | Download Citation

Subjects

Abstract

Mammalian organs comprise an extraordinary diversity of cell and tissue types. Regenerative organs, such as the skin and gastrointestinal tract, use resident stem cells to maintain tissue function. Organs with a lower cellular turnover, such as the liver and lungs, mostly rely on proliferation of committed progenitor cells. In many organs, injury reveals the plasticity of both resident stem cells and differentiated cells. The ability of resident cells to maintain and repair organs diminishes with age, whereas, paradoxically, the risk of cancer increases. New therapeutic approaches aim to harness cell plasticity for tissue repair and regeneration while avoiding the risk of malignant transformation of cells.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Cossu, G. et al. Lancet commission: stem cells and regenerative medicine. Lancet 391, 883–910 (2017).

  2. 2.

    Mandai, M. et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 376, 1038–1046 (2017).

  3. 3.

    Hirsch, T. et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature 551, 327–332 (2017). A combination of gene and cell therapy is used to repair most of the epidermis of a child with a skin blistering disorder.

  4. 4.

    Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).

  5. 5.

    Lane, S. W., Williams, D. A. & Watt, F. M. Modulating the stem cell niche for tissue regeneration. Nat. Biotechnol. 32, 795–803 (2014).

  6. 6.

    Rajagopal, J. & Stanger, B. Z. Plasticity in the adult: how should the Waddington diagram be applied to regenerating tissues? Dev. Cell 36, 133–137 (2016).

  7. 7.

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

  8. 8.

    Rognoni, E. et al. Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing. Development 143, 2522–2535 (2016).

  9. 9.

    Merrell, A. J. & Stanger, B. Z. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat. Rev. Mol. Cell Biol. 17, 413–425 (2016).

  10. 10.

    Donati, G. et al. Wounding induces dedifferentiation of epidermal Gata6+ cells and acquisition of stem cell properties. Nat. Cell Biol. 19, 603–613 (2017). Demonstration that terminally differentiated cells of the sebaceous duct can dedifferentiate and contribute to long-term repopulation of the interfollicular epidermis during wound repair.

  11. 11.

    Li, N., Nakauka-Ddamba, A., Tobias, J., Jensen, S. T. & Lengner, C. J. Mouse label-retaining cells are molecularly and functionally distinct from reserve intestinal stem cells. Gastroenterology 151, 298–310 (2016).

  12. 12.

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

  13. 13.

    Signer, R. A., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49–54 (2014).

  14. 14.

    Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013).

  15. 15.

    Lee, J. H. et al. Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell 170, 1149–1163 (2017).

  16. 16.

    Leushacke, M. et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat. Cell Biol. 19, 774–786 (2017).

  17. 17.

    Cao, W. et al. Dynamics of proliferative and quiescent stem cells in liver homeostasis and injury. Gastroenterology 153, 1133–1147 (2017).

  18. 18.

    Huch, M. et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 32, 2708–2721 (2013).

  19. 19.

    He, L. et al. Enhancing the precision of genetic lineage tracing using dual recombinases. Nat. Med. 23, 1488–1498 (2017). A lineage tracing strategy that depends on the co-expression of two different recombinases can target more specific populations of stem and progenitor cells.

  20. 20.

    Lu, W. Y. et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat. Cell Biol. 17, 971–983 (2015).

  21. 21.

    Raven, A. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547, 350–354 (2017). When hepatocyte proliferation is impaired, biliary cells can contribute to regeneration of both bile ducts and hepatocytes.

  22. 22.

    Pei, W. et al. Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548, 456–460 (2017). The authors use a Cre– loxP approach to genetically barcode thousands of individual haematopoietic stem cells and follow their descendants in vivo.

  23. 23.

    McKenna, A. et al. Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353, aaf7907 (2016).

  24. 24.

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

  25. 25.

    Simons, B. D. Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis. Proc. Natl Acad. Sci. USA 113, 128–133 (2016).

  26. 26.

    Lynch, M. D. et al. Spatial constraints govern competition of mutant clones in human epidermis. Nat. Commun. 8, 1119 (2017). The size of some clones in cancer-prone epidermis is too large to be accounted for by neutral drift.

  27. 27.

    Regev, A. et al. The human cell atlas. eLife 6, e27041 (2017).

  28. 28.

    Tata, P. R. & Rajagopal, J. Plasticity in the lung: making and breaking cell identity. Development 144, 755–766 (2017).

  29. 29.

    Kretzschmar, K., Weber, C., Driskell, R. R., Calonje, E. & Watt, F. M. Compartmentalized epidermal activation of β-catenin differentially affects lineage reprogramming and underlies tumor heterogeneity. Cell Rep. 14, 269–281 (2016).

  30. 30.

    Lichtenberger, B. M., Mastrogiannaki, M. & Watt, F. M. Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages. Nat. Commun. 7, 10537 (2016).

  31. 31.

    Telerman, S. B. et al. Dermal Blimp1 acts downstream of epidermal TGFβ and Wnt/β-catenin to regulate hair follicle formation and growth. J. Invest. Dermatol. 137, 2270–2281 (2017).

  32. 32.

    Demcollari, T. I., Cujba, A. M. & Sancho, R. Phenotypic plasticity in the pancreas: new triggers, new players. Curr. Opin. Cell Biol. 49, 38–46 (2017).

  33. 33.

    Zhou, Q. et al. A multipotent progenitor domain guides pancreatic organogenesis. Dev. Cell 13, 103–114 (2007).

  34. 34.

    Sancho, R., Gruber, R., Gu, G. & Behrens, A. Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells. Cell Stem Cell 15, 139–153 (2014).

  35. 35.

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

  36. 36.

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

  37. 37.

    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).

  38. 38.

    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).

  39. 39.

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

  40. 40.

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

  41. 41.

    Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017). The ability of myofibroblasts to convert to adipocytes is unexpected, because the two cell types were thought to represent distinct lineages.

  42. 42.

    Mastrogiannaki, M. et al. β-Catenin stabilization in skin fibroblasts causes fibrotic lesions by preventing adipocyte differentiation of the reticular dermis. J. Invest. Dermatol. 136, 1130–1142 (2016).

  43. 43.

    Michael, S., Achilleos, C., Panayiotou, T. & Strati, K. Inflammation shapes stem cells and stemness during infection and beyond. Front. Cell Dev. Biol. 4, 118 (2016).

  44. 44.

    Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).

  45. 45.

    Aurora, A. B. & Olson, E. N. Immune modulation of stem cells and regeneration. Cell Stem Cell 15, 14–25 (2014).

  46. 46.

    Shook, B., Xiao, E., Kumamoto, Y., Iwasaki, A. & Horsley, V. CD301b+ macrophages are essential for effective skin wound healing. J. Invest. Dermatol. 136, 1885–1891 (2016).

  47. 47.

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

  48. 48.

    Patel, A. S. et al. TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb. EMBO Mol. Med. 5, 858–869 (2013).

  49. 49.

    Cosin-Roger, J. et al. Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nat. Commun. 8, 98 (2017).

  50. 50.

    Jia, J. et al. LGR5 expression is controled by IKKα in basal cell carcinoma through activating STAT3 signaling pathway. Oncotarget 7, 27280–27294 (2016).

  51. 51.

    Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).

  52. 52.

    Naik, S. et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017). Inflammation can trigger the epigenetic memory of injury by maintaining chromosomal accessibility to key stress-response genes.

  53. 53.

    Meng, S., Chanda, P., Thandavarayan, R. A. & Cooke, J. P. Transflammation: innate immune signaling in nuclear reprogramming. Adv. Drug Deliv. Rev. 120, 133–141 (2017).

  54. 54.

    Ori, D., Murase, M. & Kawai, T. Cytosolic nucleic acid sensors and innate immune regulation. Int. Rev. Immunol. 36, 74–88 (2017).

  55. 55.

    Yang, H., Adam, R. C., Ge, Y., Hua, Z. L. & Fuchs, E. Epithelial–mesenchymal micro-niches govern stem cell lineage choices. Cell 169, 483–496 (2017).

  56. 56.

    Viswanathan, P. et al. Mimicking the topography of the epidermal-dermal interface with elastomer substrates. Integr. Biol. (Camb.) 8, 21–29 (2016).

  57. 57.

    Miroshnikova, Y. A. et al. Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Nat. Cell Biol. 20, 69–80 (2018).

  58. 58.

    Gudipaty, S. A. et al. Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature 543, 118–121 (2017).

  59. 59.

    Panciera, T. et al. Induction of expandable tissue-specific stem/progenitor cells through transient expression of YAP/TAZ. Cell Stem Cell 19, 725–737 (2016).

  60. 60.

    Walko, G. et al. A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells. Nat. Commun. 8, 14744 (2017).

  61. 61.

    Totaro, A. et al. YAP/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate. Nat. Commun. 8, 15206 (2017).

  62. 62.

    Yui, S. et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell 22, 35–49 (2018).

  63. 63.

    Liu, X. et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am. J. Pathol. 180, 599–607 (2012).

  64. 64.

    Wang, X. et al. Cloning and variation of ground state intestinal stem cells. Nature 522, 173–178 (2015).

  65. 65.

    Mou, H. et al. Dual SMAD signaling inhibition enables long-term expansion of diverse epithelial basal cells. Cell Stem Cell 19, 217–231 (2016).

  66. 66.

    Owens, D. M., Romero, M. R., Gardner, C. & Watt, F. M. Suprabasal α6β4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFβ signalling. J. Cell Sci. 116, 3783–3791 (2003).

  67. 67.

    Schultz, M. B. & Sinclair, D. A. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development 143, 3–14 (2016).

  68. 68.

    Avgustinova, A. & Benitah, S. A. Epigenetic control of adult stem cell function. Nat. Rev. Mol. Cell Biol. 17, 643–658 (2016).

  69. 69.

    Tilly, J. L. & Sinclair, D. A. Germline energetics, aging, and female infertility. Cell Metab. 17, 838–850 (2013).

  70. 70.

    Tomasetti, C. & Vogelstein, B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).

  71. 71.

    Yang, T. B. et al. Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche. Nat. Commun. 8, 14766 (2017).

  72. 72.

    Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

  73. 73.

    Rebo, J. et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat. Commun. 7, 13363 (2016).

  74. 74.

    Neves, J., Sousa-Victor, P. & Jasper, H. Rejuvenating strategies for stem cell-based therapies in aging. Cell Stem Cell 20, 161–175 (2017).

  75. 75.

    Zhang, Y. et al. Development and stem cells of the esophagus. Semin. Cell Dev. Biol. 66, 25–35 (2017).

  76. 76.

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

  77. 77.

    Watanabe, M. et al. Type XVII collagen coordinates proliferation in the interfollicular epidermis. eLife 6, e26635 (2017).

  78. 78.

    Nalapareddy, K. et al. Canonical Wnt signaling ameliorates aging of intestinal stem cells. Cell Rep. 18, 2608–2621 (2017).

  79. 79.

    Scudellari, M. To stay young, kill zombie cells. Nature 550, 448–450 (2017).

  80. 80.

    Latil, M. 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 (2017).

  81. 81.

    Brown, S. et al. Correction of aberrant growth preserves tissue homeostasis. Nature 548, 334–337 (2017). Demonstration that wild-type cells are involved in actively eliminating cells with an activating β-catenin mutation from the epidermis.

  82. 82.

    Radyk, M. D., Burclaff, J., Willet, S. G. & Mills, J. C. Metaplastic cells in the stomach arise, independently of stem cells, via dedifferentiation or transdifferentiation of chief cells. Gastroenterology 154, 839–843 (2018).

  83. 83.

    Jiang, M. et al. Transitional basal cells at the squamous–columnar junction generate Barrett’s oesophagus. Nature 550, 529–533 (2017).

  84. 84.

    Duarte, D. et al. Inhibition of endosteal vascular niche remodelling rescues hematopoietic stem cell loss in AML. Cell Stem Cell 22, 64–77 (2017). Pharmacologic manipulation of the haematopoietic stem cell niche to preserve normal function is a new paradigm for treating acute myeloid leukemia.

  85. 85.

    Mishra, A. et al. A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis. eLife 6, e27356 (2017).

  86. 86.

    Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).

  87. 87.

    Rubino, F. & Amiel, S. A. Is the gut the “sweet spot” for the treatment of diabetes? Diabetes 63, 2225–2228 (2014).

  88. 88.

    Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25–36 (2010).

  89. 89.

    Sigal, M. et al. Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature 548, 451–455 (2017).

  90. 90.

    Arnold, K. et al. Sox2+ adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9, 317–329 (2011).

  91. 91.

    Choi, E. et al. Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut https://doi.org/10.1136/gutjnl-2017-313874 (2017).

  92. 92.

    Hayakawa, Y. et al. Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche. Cancer Cell 28, 800–814 (2015).

  93. 93.

    Wang, B., Zhao, L., Fish, M., Logan, C. Y. & Nusse, R. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524, 180–185 (2015). This study showed that a subpopulation of Wnt-responsive hepatocytes broadly contributes to normal liver maintenance.

  94. 94.

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

  95. 95.

    Zorn, A. M. & Wells, J. M. Vertebrate endoderm development and organ formation. Annu. Rev. Cell Dev. Biol. 25, 221–251 (2009).

  96. 96.

    Simmini, S. et al. Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2. Nat. Commun. 5, 5728 (2014). This study demonstrated that one gene, Cdx2 , functionally distinguishes between intestinal stem cells and gastric stem cells.

  97. 97.

    Wells, J. M. Developmental biology: regional identity of gut stem cells—one gene to rule them all. Nat. Rev. Gastroenterol. Hepatol. 12, 125–126 (2015).

  98. 98

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

Download references

Acknowledgements

F.M.W. acknowledges funding from the Wellcome Trust (206439/Z/17/Z), Medical Research Council (MR/PO18823/1), Cancer Research UK (C219/A23522) and the Biotechnology and Biological Sciences Research Council (BB/M007219/1). J.M.W. is supported by grants from the National Institutes of Health R01DK092456, U19AI116491, P01HD093363 and U01DK103117. We thank C. Mooney for help with the Figures.

Reviewer information

Nature thanks C. Lengner and J. Rajagopal for their contribution to the peer review of this work.

Author information

Affiliations

  1. Divisions of Developmental Biology and Endocrinology, Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

    • James M. Wells
  2. Centre for Stem Cells and Regenerative Medicine, Guy’s Hospital Campus, King’s College London, London, UK

    • Fiona M. Watt

Authors

  1. Search for James M. Wells in:

  2. Search for Fiona M. Watt in:

Contributions

J.M.W. and F.M.W. conceived and wrote the manuscript and drafted the Figures together.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to James M. Wells or Fiona M. Watt.

About this article

Publication history

Received

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41586-018-0073-7

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.