The myofibroblast, multiple origins for major roles in normal and pathological tissue repair
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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.
KeywordsMesenchymal Stem Cell Stress Fiber Hepatic Stellate Cell Hypertrophic Scar Epithelial Stem Cell
List of abbreviations used
epithelial- and endothelial-to-mesenchymal transition
precision cut-liver slice
transforming growth factor
tissue inhibitor of metalloproteinases.
Tissue repair is an essential phenomenon allowing tissues and organs to recover functional properties that have been lost after an injury, either linked to a wound or to a disease. Contrary to what is seen in fetal or embryonic wounds that repair without a scar or fibrosis, normal repair in the adult always leads to scar formation, the consequence of which may be defects in functionality (e.g. skin hypertrophic scar or fibrosis). In these processes, fibroblasts/myofibroblats play a crucial role. Moreover, myofibroblasts are instrumental in the stroma reaction to epithelial tumors and are now thought to promote cancer progression by creating a stimulating microenvironment for the transformed cells [1, 2].
The myofibroblast in normal and pathological situations
Normal wound healing
Pathological wound healing can be encountered in a variety of disease states . These abnormal repair processes are the result of an impaired remodelling of the granulation tissue leading for example to abnormal cutaneous repair as seen in hypertrophic scarring or to fibrosis in internal organs such as the liver, lung and kidney. In hypertrophic scars, numerous myofibroblasts express α-smooth muscle actin, explaining the frequent appearance of contracture . In internal organs, after an acute and moderate lesion, the injured tissue may be almost completely restored to normal. The repair process involved is globally similar to the process observed in cutaneous wounding. However, when the noxious stimulus responsible for the lesion persists, excessive extracellular matrix deposition and the continued presence of myofibroblasts is observed. This excess of extracellular matrix deposition leads to the development of organ fibrosis. For example, in the liver, several chronic diseases (chronic viral hepatitis, alcoholic disease and cholestasis) are responsible for the development of a significant fibrosis whose ultimate stage, cirrhosis, has a substantial impact on morbidity and mortality. As in pathological cutaneous wound healing, the installation and persistence of fibrosis is the consequence of an imbalance between extracellular matrix synthesis and degradation by myofibroblasts. In this situation the balance of MMPs/TIMPs plays an essential role. For example, throughout hepatic fibrogenesis, an increase of TIMP-1 and TIMP-2 expression without any modification of MMP-1 is observed and it is thought that this leads to excessive matrix deposition.
Cytokines involved in myofibroblast differentiation
Various cytokines and growth factors have a role in wound healing and scarring . Among these soluble factors some directly act on granulation tissue formation and fibrogenic cell activation, especially transforming growth factor (TGF)-β1, a potent inducer of myofibroblastic differentiation . Beyond a specific effect on the induction of α-smooth muscle expression, TGF-β1 also promotes the deposition of large amounts of extracellular matrix; in fact, TGF-β1 not only induces synthesis of extracellular matrix, particularly fibrillar collagens and fibronectin but it also reduces MMP activity by promoting TIMP expression. It is important to note that TGF-β1 action on myofibroblastic differentiation is only possible in the presence of the ED-A splice variant fibronectin which underlines the fact that extracellular matrix components play an important role in soluble factor activity . More recently, it has been shown that granulation tissue formation is modified by chemical denervation . This peripheral nervous system involvement in tissue repair has likewise been shown in the liver, where in this organ, in an experimental model of fibrosis using carbon tetrachloride treatment, chemical denervation significantly reduces matrix deposition and myofibroblastic differentiation .
Role of mechanical stress
Myofibroblastic cells, because of their contractile properties and their privileged relationship with the extracellular matrix, can modify their activity depending on the mechanical environment. Although this is an essential point, it still remains poorly investigated. It has been shown, in gingival fibroblasts, that α-smooth muscle actin expression induced by TGF-β1 is regulated by the compliance of collagen gels on or in which they are cultured . Moreover, myofibroblastic differentiation features, such as stress fibers, ED-A fibronectin or α-smooth muscle expression, appear earlier in granulation tissue subjected to an increase in mechanical tension by splinting of a full-thickness wound with a plastic frame as compared to normally healing wounds . It has also been shown that fibroblasts cultured on substrates of variable stiffness present different phenotypes. Cultured fibroblasts do not express stress fibers on soft surfaces; whilst when the stiffness of the substrate increases, a sudden change in cell morphology occurs and stress fibers appear [17, 18]. More recently, it has been shown that shear forces exerted by fluid flow are also able to induce TGF-β1 production and differentiation of fibroblasts cultured in collagen gels in the absence of other external stimuli such as cytokine treatment .
Origin of the myofibroblast
Conclusions and perspectives
The fibroblast/myofibroblast transition is accepted as the key event in the formation of granulation tissue during wound healing or fibrotic changes, but also during the evolution of the stroma reaction in cancer. Though different experimental models have been developed, until now, the exact origin of the (myo)fibroblastic cells involved in the formation of the stroma reaction observed in carcinomas is unknown. Obviously, local fibroblasts present in the connective tissue of the organ are involved. However, it has also been shown that bone marrow-derived myofibroblasts contribute to the stroma reaction [35, 36]. Interestingly, the question arises as to why the stroma reaction is scanty in hepatocellular carcinoma but abundant in cholangiocarcinoma. It is conceivable that the cells contributing to the myofibroblastic population and which participate in the stroma reaction are different in these two tumors. We suggest that hepatic stellate cell-derived myofibroblasts and portal fibroblast-derived myofibroblasts are involved in the stroma reactions encountered in hepatocellular carcinoma and cholangiocarcinoma, respectively, and we have recently performed a proteomic study in order to make progress in this field . All of this information is required for the development of treatments that could specifically and efficiently target the cells responsible for the development of fibrotic diseases and of the stroma reaction in cancers. Indeed, stroma-myofibroblast interactions represent an interesting tumor differentiation-independent target for therapy of cancers, particularly for hepatocellular carcinoma and cholangiocarcinoma which are highly aggressive cancers.
BC, IAD, and AD have worked on mechanisms involved in tissue repair and fibroblast subpopulations for over 20 years. LM has developed with BC and AD, research on mesenchymal stem/stromal cells and their roles in tissue repair. NV and FB performed studies on matrix metalloproteinases and their inhibitors.
This article has been published as part of Fibrogenesis & Tissue Repair Volume 5 Supplement 1, 2012: Proceedings of Fibroproliferative disorders: from biochemical analysis to targeted therapies. The full contents of the supplement are available online at http://www.fibrogenesis.com/supplements/5/S1.
This work was supported in part by a grant from the University of Limoges (Contrat Renforcé Recherche), the Fondation des "Gueules Cassées" (Paris, France), and CASCADE (7th European Framework Programme, N° 223236). IAD was supported in part by the Australian Academy of Sciences (2007), and the University of Limoges (Invited Professor, 2008). NV was recipient of a fellowship from Région Limousin.
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