The myofibroblast, multiple origins for major roles in normal and pathological tissue repair

Ludovic Micallef, Nicolas Vedrenne, Fabrice Billet, Bernard Coulomb, Ian A Darby, Alexis Desmoulière, Ludovic Micallef, Nicolas Vedrenne, Fabrice Billet, Bernard Coulomb, Ian A Darby, Alexis Desmoulière

Abstract

Myofibroblasts differentiate, invade and repair injured tissues by secreting and organizing the extracellular matrix and by developing contractile forces. When tissues are damaged, tissue homeostasis must be re-established, and repair mechanisms have to rapidly provide harmonious mechanical tissue organization, a process essentially supported by (myo)fibroblasts. Under physiological conditions, the secretory and contractile activities of myofibroblasts are terminated when the repair is complete (scar formation) but the functionality of the tissue is only rarely perfectly restored. At the end of the normal repair process, myofibroblasts disappear by apoptosis but in pathological situations, myofibroblasts likely remain leading to excessive scarring. Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair. These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases.

Figures

Figure 1
Figure 1
Schematic illustration showing the evolution of the (myo)fibroblast phenotype. The myofibroblastic modulation of fibroblastic cells begins with the appearance of the proto-myofibroblast, whose stress fibers contain only β- and γ-cytoplasmic actins and evolves, but not necessarily always, into the appearance of the differentiated myofibroblast, the most common variant of this cell, with stress fibers containing α-smooth muscle actin. The myofibroblast may disappear by apoptosis; the deactivation leading to a quiescent phenotype has not been clearly demonstrated at least in vivo. TGF-β1: transforming growth factor-β1; ECM: extracellular matrix. Modified from [38].
Figure 2
Figure 2
Myofibroblast origins. The main myofibroblast progenitor after injury of different tissues appears to be locally residing fibroblasts. Indeed, various cell types can acquire a myofibroblastic phenotype; these diverse origins lead to distinct myofibroblast sub-populations. EMT: epithelial- and endothelial-to-mesenchymal transition.

References

    1. Desmoulière A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol. 2004;48:509–517. doi: 10.1387/ijdb.041802ad.
    1. Hinz B, Darby IA, Gabbiani G, Desmoulière A. In: Tumor Associated Fibroblasts and their Matrix. Fusenig NE, Mueller MM, editor. New York: Springer; 2011. The role of the myofibroblast in fibrosis and cancer progression; pp. 37–74.
    1. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–321. doi: 10.1038/nature07039.
    1. Hinz B. The myofibroblast: paradigm for a mechanically active cell. J Biomech. 2010;43:146–155. doi: 10.1016/j.jbiomech.2009.09.020.
    1. Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol. 2007;127:526–537. doi: 10.1038/sj.jid.5700613.
    1. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3:349–363. doi: 10.1038/nrm809.
    1. Darby IA, Bisucci T, Pittet B, Garbin S, Gabbiani G, Desmoulière A. Skin flap-induced regression of granulation tissue correlates with reduced growth factor and increased metalloproteinase expression. J Pathol. 2002;197:117–127. doi: 10.1002/path.1074.
    1. Desmoulière A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol. 1995;146:56–66.
    1. Sarrazy V, Billet F, Coulomb B, Desmoulière A. Mechanisms of pathological scarring: role of myofibroblasts and current developments. Wound Repair Regen. 2011;19(Suppl 1):s10–15.
    1. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83:835–870.
    1. Desmoulière A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122:103–111. doi: 10.1083/jcb.122.1.103.
    1. Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol. 1998;142:873–881. doi: 10.1083/jcb.142.3.873.
    1. Souza BR, Cardoso JF, Amadeu TP, Desmoulière A, Costa AM. Sympathetic denervation accelerates wound contraction but delays reepithelialization in rats. Wound Repair Regen. 2005;13:498–505. doi: 10.1111/j.1067-1927.2005.00070.x.
    1. Dubuisson L, Desmoulière A, Decourt B, Evadé L, Bedin C, Boussarie L, Barrier L, Vidaud M, Rosenbaum J. Inhibition of liver fibrogenesis through noradrenergic antagonism. Hepatology. 2002;35:325–331. doi: 10.1053/jhep.2002.31166.
    1. Arora PD, Narani N, McCulloch CA. The compliance of collagen gels regulates transforming growth factor-β induction of α-smooth muscle actin in fibroblasts. Am J Pathol. 1999;154:871–882. doi: 10.1016/S0002-9440(10)65334-5.
    1. Hinz B, Mastrangelo D, Iselin CE, Chaponnier C, Gabbiani G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol. 2001;159:1009–1020. doi: 10.1016/S0002-9440(10)61776-2.
    1. Wells RG. The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol. 2005;39(4 Suppl 2):s158–161.
    1. Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M, Zahir N, Ming W, Weaver V, Janmey PA. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil Cytoskeleton. 2005;60:24–34. doi: 10.1002/cm.20041.
    1. Ng CP, Hinz B, Swartz MA. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J Cell Sci. 2005;118:4731–4739. doi: 10.1242/jcs.02605.
    1. Sorrell JM, Caplan AI. Fibroblast heterogeneity: more than skin deep. J Cell Sci. 2004;117:667–675. doi: 10.1242/jcs.01005.
    1. Guyot C, Lepreux S, Combe C, Doudnikoff E, Bioulac-Sage P, Balabaud C, Desmoulière A. Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involved. Int J Biochem Cell Biol. 2006;38:135–151.
    1. Guyot C, Combe C, Balabaud C, Bioulac-Sage P, Desmoulière A. Fibrogenic cell fate during fibrotic tissue remodelling observed in rat and human cultured liver slices. J Hepatol. 2007;46:142–150. doi: 10.1016/j.jhep.2006.08.013.
    1. Guyot C, Lepreux S, Combe C, Sarrazy V, Billet F, Balabaud C, Bioulac-Sage P, Desmoulière A. Fibrogenic cell phenotype modifications during remodelling of normal and pathological human liver in cultured slices. Liver Int. 2010;30:1529–1540. doi: 10.1111/j.1478-3231.2010.02342.x.
    1. Desmoulière A. Hepatic stellate cells: the only cells involved in liver fibrogenesis? A dogma challenged. Gastroenterology. 2007;132:2059–2062. doi: 10.1053/j.gastro.2007.03.075.
    1. Jahoda C, Reynolds A. Hair follicle dermal sheath cells: unsung participants in wound healing. Lancet. 2001;358:1445–1448. doi: 10.1016/S0140-6736(01)06532-1.
    1. Saxena R, Theise N. Canals of Hering: recent insights and current knowledge. Sem Liver Dis. 2004;24:43–48.
    1. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol. 2001;166:7556–7562.
    1. Yang L, Scott PG, Dodd C, Medina A, Jiao H, Shankowsky HA, Ghahary A, Tredget EE. Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen. 2005;13:398–404. doi: 10.1111/j.1067-1927.2005.130407.x.
    1. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol. 2003;171:380–389.
    1. Okada H, Kalluri R. Cellular and molecular pathways that lead to progression and regression of renal fibrogenesis. Curr Mol Med. 2005;5:467–474. doi: 10.2174/1566524054553478.
    1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147. doi: 10.1126/science.284.5411.143.
    1. Direkze NC, Forbes SJ, Brittan M, Hunt T, Jeffery R, Preston SL, Poulsom R, Hodivala-Dilke K, Alison MR, Wright NA. Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice. Stem Cells. 2003;21:514–520. doi: 10.1634/stemcells.21-5-514.
    1. Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology. 2004;126:955–963. doi: 10.1053/j.gastro.2004.02.025.
    1. Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 2010;21:212–222. doi: 10.1681/ASN.2008121226.
    1. Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N, Endoh Y, Okumura C, Okuhara Y, Magae J, Emura M, Ochiya T, Ochiai A. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun. 2003;309:232–240. doi: 10.1016/S0006-291X(03)01544-4.
    1. Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR, Wright NA. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 2004;64:8492–8495. doi: 10.1158/0008-5472.CAN-04-1708.
    1. Darby IA. Vuillier-Devillers K, Pinault E, Sarrazy V, Lepreux S, Balabaud C, Bioulac-Sage P, Desmoulière A. Proteomic analysis of differentially expressed proteins in peripheral cholangiocarcinoma. Cancer Microenviron. 2010;4:73–91. doi: 10.1007/s12307-010-0047-2.
    1. Guyot C, Lepreux S, Darby IA, Desmoulière A. In: The Cancer Handbook. 2. Alison MR, editor. Chichester: John Wiley & Sons; 2007. The biology of tumor stroma; pp. 155–167.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner