Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Preparing the ground for tissue regeneration: from mechanism to therapy

Abstract

Chronic diseases confer tissue and organ damage that reduce quality of life and are largely refractory to therapy. Although stem cells hold promise for treating degenerative diseases by 'seeding' injured tissues, the regenerative capacity of stem cells is influenced by regulatory networks orchestrated by local immune responses to tissue damage, with macrophages being a central component of the injury response and coordinator of tissue repair. Recent research has turned to how cellular and signaling components of the local stromal microenvironment (the 'soil' to the stem cells' seed), such as local inflammatory reactions, contribute to successful tissue regeneration. This Review discusses the basic principles of tissue regeneration and the central role locally acting components may play in the process. Application of seed-and-soil concepts to regenerative medicine strengthens prospects for developing cell-based therapies or for promotion of endogenous repair.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: General model of tissue repair.

Debbie Maizels / Nature Publishing Group

Figure 2: Regeneration in the normal liver and the chronically damaged liver.

Debbie Maizels / Nature Publishing Group

Figure 3: Modulation of inflammation and cell replacement in muscle regeneration (a) Muscle injury disrupts capillaries and triggers inflammatory cascades, which result in neutrophil invasion for necrotic tissue removal and M1 macrophage activation by IFN-γ and TFN.

Debbie Maizels / Nature Publishing Group

Figure 4: Ontogeny and phylogeny of tissue regenerative capacity.

Debbie Maizels / Nature Publishing Group

References

  1. Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2012).

    Article  PubMed  Google Scholar 

  2. Niethammer, P., Grabher, C., Look, A.T. & Mitchison, T.J. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459, 996–999 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Pase, L. et al. Neutrophil-delivered myeloperoxidase dampens the hydrogen peroxide burst after tissue wounding in zebrafish. Curr. Biol. 22, 1818–1824 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Skaper, S.D., Facci, L. & Giusti, P. Mast cells, glia and neuroinflammation: partners in crime? Immunology 141, 314–327 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wulff, B.C. & Wilgus, T.A. Mast cell activity in the healing wound: more than meets the eye? Exp. Dermatol. 22, 507–510 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Porta, C. et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB. Proc. Natl. Acad. Sci. USA 106, 14978–14983 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Martinez, F.O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wynn, T.A., Chawla, A. & Pollard, J.W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mosser, D.M. & Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Davies, L.C., Jenkins, S.J., Allen, J.E. & Taylor, P.R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jenkins, S.J. et al. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. J. Exp. Med. 210, 2477–2491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jenkins, S.J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li, L., Yan, B., Shi, Y.Q., Zhang, W.Q. & Wen, Z.L. Live imaging reveals differing roles of macrophages and neutrophils during zebrafish tail fin regeneration. J. Biol. Chem. 287, 25353–25360 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hay, E.D. & Fischman, D.A. Origin of the blastema in regenerating limbs of the newt Triturus viridescens. An autoradiographic study using tritiated thymidine to follow cell proliferation and migration. Dev. Biol. 3, 26–59 (1961).

    Article  CAS  PubMed  Google Scholar 

  17. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Chen, C.W. et al. Perivascular multi-lineage progenitor cells in human organs: regenerative units, cytokine sources or both? Cytokine Growth Factor Rev. 20, 429–434 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Dulauroy, S., Di Carlo, S.E., Langa, F., Eberl, G. & Peduto, L. Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat. Med. 18, 1262–1270 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Lin, S.L., Kisseleva, T., Brenner, D.A. & Duffield, J.S. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am. J. Pathol. 173, 1617–1627 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Henderson, N.C. et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Göritz, C. et al. A pericyte origin of spinal cord scar tissue. Science 333, 238–242 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Issa, R. et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCL4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J. 17, 47–49 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Kallis, Y.N. et al. Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Gut 60, 525–533 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Pellicoro, A., Ramachandran, P., Iredale, J.P. & Fallowfield, J.A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 14, 181–194 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Stark, K. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs. Nat. Immunol. 14, 41–51 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Dellavalle, A. et al. Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat. Commun. 2, 499 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Cappellari, O. et al. Dll4 and PDGF-BB convert committed skeletal myoblasts to pericytes without erasing their myogenic memory. Dev. Cell 24, 586–599 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Katare, R. et al. Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circ. Res. 109, 894–906 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Corselli, M., Chen, C.W., Crisan, M., Lazzari, L. & Peault, B. Perivascular ancestors of adult multipotent stem cells. Arterioscler. Thromb. Vasc. Biol. 30, 1104–1109 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Wing, K. & Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 11, 7–13 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Josefowicz, S.Z., Lu, L.F. & Rudensky, A.Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Burzyn, D., Benoist, C. & Mathis, D. Regulatory T cells in nonlymphoid tissues. Nat. Immunol. 14, 1007–1013 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tang, T.T. et al. Regulatory T cells ameliorate cardiac remodeling after myocardial infarction. Basic Res. Cardiol. 107, 232 (2012).

    Article  PubMed  Google Scholar 

  36. Michalopoulos, G.K. & DeFrances, M.C. Liver regeneration. Science 276, 60–66 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Bird, T.G., Lorenzini, S. & Forbes, S.J. Activation of stem cells in hepatic diseases. Cell Tissue Res. 331, 283–300 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Boulton, R.A., Alison, M.R., Golding, M., Selden, C. & Hodgson, H.J. Augmentation of the early phase of liver regeneration after 70% partial hepatectomy in rats following selective Kupffer cell depletion. J. Hepatol. 29, 271–280 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Boulton, R. et al. Nonparenchymal cells from regenerating rat liver generate interleukin-1α and -1β: a mechanism of negative regulation of hepatocyte proliferation. Hepatology 26, 49–58 (1997).

    CAS  PubMed  Google Scholar 

  40. Meijer, C. et al. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver 20, 66–77 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Goh, Y.P. et al. Eosinophils secrete IL-4 to facilitate liver regeneration. Proc. Natl. Acad. Sci. USA 110, 9914–9919 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Higgins, G.M. & Anderson, R.M. Experimental pathology of the liver: restoration of the liver of the white rat following partial removal. Arch. Pathol. (Chic.) 12, 186–202 (1931).

    Google Scholar 

  43. Yamanaka, N. et al. Dynamics of normal and injured human liver regeneration after hepatectomy as assessed on the basis of computed tomography and liver function. Hepatology 18, 79–85 (1993).

    Article  CAS  PubMed  Google Scholar 

  44. Ding, B.S. et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468, 310–315 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hu, J. et al. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 343, 416–419 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Ding, B.S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Passino, M.A., Adams, R.A., Sikorski, S.L. & Akassoglou, K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 315, 1853–1856 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Ochoa, B. et al. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology 51, 1712–1723 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Issa, R. et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J. 17, 47–49 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Boulter, L. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18, 572–579 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tsuchiya, A. et al. PolySia-NCAM modulates the formation of ductular reactions in liver injury. Hepatology doi:10.1002/hep.27099 (28 February 2014).

  52. Williams, M.J., Clouston, A.D. & Forbes, S.J. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 146, 349–356 (2014).

    Article  PubMed  Google Scholar 

  53. Iredale, J.P., Murphy, G., Hembry, R.M., Friedman, S.L. & Arthur, M.J. Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1. Implications for regulation of matrix degradation in liver. J. Clin. Invest. 90, 282–287 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Iredale, J.P. et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Invest. 102, 538–549 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fallowfield, J.A. et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178, 5288–5295 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl. Acad. Sci. USA 109, 9448–9453 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Duffield, J.S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gibbons, M.A. et al. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am. J. Respir. Crit. Care Med. 184, 569–581 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl. Acad. Sci. USA 109, E3186–E3195 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Overturf, K., al-Dhalimy, M., Ou, C.N., Finegold, M. & Grompe, M. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am. J. Pathol. 151, 1273–1280 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Bird, T.G. et al. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Proc. Natl. Acad. Sci. USA 110, 6542–6547 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Espanol-Suner, R. et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143, 1564–1575.e7 (2012).

    Article  PubMed  Google Scholar 

  63. He, J., Lu, H., Zou, Q. & Luo, L. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 146, 789–800.e8 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Choi, T.Y., Ninov, N., Stainier, D.Y. & Shin, D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 146, 776–788 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Huch, M. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yanger, K. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 27, 719–724 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. 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 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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 

  75. Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141, 1762–1772 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Jung, P. et al. Isolation and in vitro expansion of human colonic stem cells. Nat. Med. 17, 1225–1227 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Sala, F.G. et al. A multicellular approach forms a significant amount of tissue-engineered small intestine in the mouse. Tissue Eng. Part A 17, 1841–1850 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. MacDonald, T.T., Monteleone, I., Fantini, M.C. & Monteleone, G. Regulation of homeostasis and inflammation in the intestine. Gastroenterology 140, 1768–1775 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Pull, S.L., Doherty, J.M., Mills, J.C., Gordon, J.I. & Stappenbeck, T.S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl. Acad. Sci. USA 102, 99–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Lu, N. et al. Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis. J. Immunol. 192, 1013–1023 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Seno, H. et al. Efficient colonic mucosal wound repair requires Trem2 signaling. Proc. Natl. Acad. Sci. USA 106, 256–261 (2009).

    Article  PubMed  Google Scholar 

  83. Egea, L. et al. GM-CSF produced by nonhematopoietic cells is required for early epithelial cell proliferation and repair of injured colonic mucosa. J. Immunol. 190, 1702–1713 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Willenborg, S. & Eming, S.A. Macrophages—sensors and effectors coordinating skin damage and repair. J. Dtsch. Dermatol. Ges. 12, 214–221 (2014).

    PubMed  Google Scholar 

  85. Lucas, T. et al. Differential roles of macrophages in diverse phases of skin repair. J. Immunol. 184, 3964–3977 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Russell, S.E. & Walsh, P.T. Sterile inflammation—do innate lymphoid cell subsets play a role? Front. Immunol. 3, 246 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Rabelink, T.J. & Little, M.H. Stromal cells in tissue homeostasis: balancing regeneration and fibrosis. Nat. Rev. Nephrol. 9, 747–753 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Anders, H.J. Immune system modulation of kidney regeneration-mechanisms and implications. Nat. Rev. Nephrol. 10, 347–358 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Romagnani, P., Lasagni, L. & Remuzzi, G. Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Nat. Rev. Nephrol. 9, 137–146 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. McCampbell, K.K. & Wingert, R.A. New tides: using zebrafish to study renal regeneration. Transl. Res. 163, 109–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. LeBleu, V.S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wang, Y. et al. Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int. 72, 290–299 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Alikhan, M.A. et al. Colony-stimulating factor-1 promotes kidney growth and repair via alteration of macrophage responses. Am. J. Pathol. 179, 1243–1256 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Carosio, S., Berardinelli, M.G., Aucello, M. & Musaro, A. Impact of ageing on muscle cell regeneration. Ageing Res. Rev. 10, 35–42 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tidball, J.G. & Villalta, S.A. Regulatory interactions between muscle and the immune system during muscle regeneration. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1173–R1187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Saclier, M. et al. Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration. Stem Cells 31, 384–396 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Massimino, M.L. et al. ED2+ macrophages increase selectively myoblast proliferation in muscle cultures. Biochem. Biophys. Res. Commun. 235, 754–759 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Villalta, S.A., Nguyen, H.X., Deng, B., Gotoh, T. & Tidball, J.G. Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum. Mol. Genet. 18, 482–496 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Lu, H. et al. Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J. 25, 358–369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sica, A., Schioppa, T., Mantovani, A. & Allavena, P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur. J. Cancer 42, 717–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Ochoa, O. et al. Delayed angiogenesis and VEGF production in Ccr2−/− mice during impaired skeletal muscle regeneration. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R651–R661 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204, 1057–1069 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ruffell, D. et al. A CREB-C/EBPb cascade induces M2 macrophage–specific gene expression and promotes muscle injury repair. Proc. Natl. Acad. Sci. USA 106, 17475–17480 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Villalta, S.A. et al. Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype. Hum. Mol. Genet. 20, 790–805 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Tidball, J.G. & Villalta, S.A. Regulatory interactions between muscle and the immune system during muscle regeneration. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1173–R1187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Swirski, F.K. & Nahrendorf, M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339, 161–166 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Taghavie-Moghadam, P.L., Butcher, M.J. & Galkina, E.V. The dynamic lives of macrophage and dendritic cell subsets in atherosclerosis. Ann. NY Acad. Sci. 1319, 19–37 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Pinto, A.R. et al. An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLoS ONE 7, e36814 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gow, D.J., Sester, D.P. & Hume, D.A. CSF-1, IGF-1, and the control of postnatal growth and development. J. Leukoc. Biol. 88, 475–481 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Santini, M.P. et al. Enhancing repair of the mammalian heart. Circ. Res. 100, 1732–1740 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Iekushi, K., Seeger, F., Assmus, B., Zeiher, A.M. & Dimmeler, S. Regulation of cardiac microRNAs by bone marrow mononuclear cell therapy in myocardial infarction. Circulation 125, 1765–1773, S1–S7 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Burchfield, J.S. et al. Interleukin-10 from transplanted bone marrow mononuclear cells contributes to cardiac protection after myocardial infarction. Circ. Res. 103, 203–211 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Zangi, L. et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat. Biotechnol. 31, 898–907 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Smart, N. et al. Myocardial regeneration: expanding the repertoire of thymosin beta4 in the ischemic heart. Ann. NY Acad. Sci. 1269, 92–101 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Kikuchi, K. & Poss, K.D. Cardiac regenerative capacity and mechanisms. Annu. Rev. Cell Dev. Biol. 28, 719–741 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Porrello, E.R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Porrello, E.R. et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl. Acad. Sci. USA 110, 187–192 (2013).

    Article  PubMed  Google Scholar 

  120. Haubner, B.J. et al. Complete cardiac regeneration in a mouse model of myocardial infarction. Aging (Albany NY) 4, 966–977 (2012).

    Article  CAS  Google Scholar 

  121. Leor, J. et al. Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation 114, I94–I100 (2006).

    Article  PubMed  Google Scholar 

  122. Cho, D.I. et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp. Mol. Med. 46, e70 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Franklin, R.J. & Ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 9, 839–855 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Czopka, T., Ffrench-Constant, C. & Lyons, D.A. Individual oligodendrocytes have only a few hours in which to generate new myelin sheaths in vivo. Dev. Cell 25, 599–609 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gibson, E.M. et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344, 1252304 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. London, A., Cohen, M. & Schwartz, M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front. Cell. Neurosci. 7, 34 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shechter, R. et al. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38, 555–569 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shechter, R., Raposo, C., London, A., Sagi, I. & Schwartz, M. The glial scar-monocyte interplay: a pivotal resolution phase in spinal cord repair. PLoS ONE 6, e27969 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Miron, V.E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Schwartz, M. & Raposo, C. Protective Autoimmunity: A unifying model for the immune network involved in CNS repair. Neuroscientist doi:10.1177/1073858413516799 (6 January 2014).

  131. Butovsky, O., Talpalar, A.E., Ben-Yaakov, K. & Schwartz, M. Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-γ and IL-4 render them protective. Mol. Cell. Neurosci. 29, 381–393 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Ziv, Y., Avidan, H., Pluchino, S., Martino, G. & Schwartz, M. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc. Natl. Acad. Sci. USA 103, 13174–13179 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Psaltis, P.J., Simari, R.D. & Rodriguez-Porcel, M. Emerging roles for integrated imaging modalities in cardiovascular cell-based therapeutics: a clinical perspective. Eur. J. Nucl. Med. Mol. Imaging 39, 165–181 (2012).

    Article  PubMed  Google Scholar 

  134. Lammers, G. et al. An overview of methods for the in vivo evaluation of tissue-engineered skin constructs. Tissue Eng. Part B Rev. 17, 33–55 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Hay, D.C. et al. Unbiased screening of polymer libraries to define novel substrates for functional hepatocytes with inducible drug metabolism. Stem Cell Res. 6, 92–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Mendelson, A. & Frenette, P.S. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat. Med. 20, 833–846 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Behfar, A., Crespo-Diaz, R., Terzic, A. & Gersh, B.J. Cell therapy for cardiac repair—lessons from clinical trials. Nat. Rev. Cardiol. 11, 232–246 (2014).

    Article  PubMed  Google Scholar 

  139. Cheng, K., Wu, F. & Cao, F. Intramyocardial autologous cell engraftment in patients with ischaemic heart failure: a meta-analysis of randomised controlled trials. Heart Lung Circ. 22, 887–894 (2013).

    Article  PubMed  Google Scholar 

  140. Rosado-de-Castro, P.H., Pimentel-Coelho, P.M., da Fonseca, L.M., de Freitas, G.R. & Mendez-Otero, R. The rise of cell therapy trials for stroke: review of published and registered studies. Stem Cells Dev. 22, 2095–2111 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Ellis, E.L. & Mann, D.A. Clinical evidence for the regression of liver fibrosis. J. Hepatol. 56, 1171–1180 (2012).

    Article  PubMed  Google Scholar 

  142. Soltys, K.A. et al. Barriers to the successful treatment of liver disease by hepatocyte transplantation. J. Hepatol. 53, 769–774 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Thomas, J.A. et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 53, 2003–2015 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Nakamura, T. et al. Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model. Gastroenterology 133, 91–107.e1 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Wang, L., Wang, X., Xie, G., Hill, C.K. & DeLeve, L.D. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J. Clin. Invest. 122, 1567–1573 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Turner, M. et al. Toward the development of a global induced pluripotent stem cell library. Cell Stem Cell 13, 382–384 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Stuart J Forbes or Nadia Rosenthal.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Forbes, S., Rosenthal, N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med 20, 857–869 (2014). https://doi.org/10.1038/nm.3653

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3653

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing