Formation and Function of the Myofibroblast during Tissue Repair

Laboratory of Cell Biophysics, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Journal of Investigative Dermatology (Impact Factor: 7.22). 04/2007; 127(3):526-37. DOI: 10.1038/sj.jid.5700613
Source: PubMed


It is generally accepted that fibroblast-to-myofibroblast differentiation represents a key event during wound healing and tissue repair. The high contractile force generated by myofibroblasts is beneficial for physiological tissue remodeling but detrimental for tissue function when it becomes excessive such as in hypertrophic scars, in virtually all fibrotic diseases and during stroma reaction to tumors. Specific molecular features as well as factors that control myofibroblast differentiation are potential targets to counteract its development, function, and survival. Such targets include alpha-smooth muscle actin and more recently discovered markers of the myofibroblast cytoskeleton, membrane surface proteins, and the extracellular matrix. Moreover, intervening with myofibroblast stress perception and transmission offers novel strategies to reduce tissue contracture; stress release leads to the instant loss of contraction and promotes apoptosis.

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    • "Please cite this article in press as: A. Watarai et al., TGFb functionalized starPEG-heparin hydrogels modulate human dermal fibroblast growth and differentiation, Acta Biomater. (2015), and Palladin were integrated in F-Actin fibers of differentiating dFb in agreement with other studies [1] [2] [5] [42]. Taken together, the reported effective administration of pre-conjugated TGFß might be used to pave the way to customized functionalized wound dressings allowing for local and sustained TGFß release and subsequently efficient myofibroblast activation. "
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    ABSTRACT: Hydrogels are promising biomaterials that can adapt easily to complex tissue entities. Furthermore, chemical modifications enable these hydrogels to become an instructive biomaterial to a variety of cell types. Human dermal fibroblasts play a pivotal role during wound healing, especially for the synthesis of novel dermal tissue replacing the primary fibrin clot. Thus, the control of growth and differentiation of dermal fibroblasts is important to modulate wound healing. In here, we utilized a versatile starPEG-heparin hydrogel platform that can be independently adjusted with respect to mechanical and biochemical properties for cultivating human dermal fibroblasts. Cell-based remodeling of the artificial matrix was ensured by using matrix metalloprotease (MMP) cleavable crosslinker peptides. Attachment and proliferation of fibroblasts on starPEG-heparin hydrogels of differing stiffness, density of pro-adhesive RGD peptides and MMP cleavable peptide linkers were tested. Binding and release of human TGFβ1 as well as biological effect of the pre-adsorbed growth factor on fibroblast gene expression and myofibroblast differentiation were investigated. Hydrogels containing RGD peptides supported fibroblast attachment, spreading, proliferation matrix deposition and remodeling compared to hydrogels without any modifications. Reversibly conjugated TGFβ1 was demonstrated to be constantly released from starPEG-heparin hydrogels for several days and capable of inducing myofibroblast differentiation of fibroblasts as determined by induction of collagen type I, ED-A-Fibronectin expression and incorporation of alpha smooth muscle actin and palladin into F-actin stress fibers. Taken together, customized starPEG-heparin hydrogels could be of value to promote dermal wound healing by stimulating growth and differentiation of human dermal fibroblasts. Copyright © 2015. Published by Elsevier Ltd.
    Acta biomaterialia 07/2015; 25. DOI:10.1016/j.actbio.2015.07.036 · 6.03 Impact Factor
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    • "Since their first description [Gabbiani et al., 1971], myofibroblasts have been shown to regulate connective tissue remodeling by combining extracellular matrix-synthesizing features of fibroblasts with contractile features similar to those of smooth muscle cells. Thus, de novo expression of a-SMA is the most widely used molecular marker of the differentiated myofibroblast [Hinz, 2007] where it is localized in stress fibers both in vitro and in vivo. Moreover, a- SMA expression correlates with force development by myofibroblasts [Hinz et al., 2001]. "
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    ABSTRACT: α-Smooth Muscle Actin (α-SMA), a widely characterized cytoskeletal protein, represents the hallmark of myofibroblast differentiation. Transforming growth factorβ1 (TGFβ1) stimulates α-SMA expression and incorporation into stress fibers, thus providing an increased myofibroblast contractile force that participates in tissue remodeling. We have addressed the molecular mechanism by which α-SMA is stably incorporated into stress fibers in human myofibroblasts following exposure to TGFβ1. The unique N-terminal sequence AcEEED, which is critical for α-SMA incorporation into stress fibers, was used to screen for AcEEED binding proteins. Tropomyosins were identified as candidate binding proteins. We find that after TGFβ1 treatment elevated levels of the Tpm1.6/7 isoforms, and to a lesser extent Tpm2.1, precede the increase in α-SMA. RNA interference experiments demonstrate that α-SMA fails to stably incorporate into stress fibers of TGFβ1 treated fibroblasts depleted of Tpm1.6/7, but not other tropomyosins. This does not appear to be due to exclusive interactions between α-SMA and just the Tpm1.6/7 isoforms. We propose that an additional AcEEED binding factor may be required to generate α-SMA filaments containing just Tpm1.6/7 which result in stable incorporation of the resulting filaments into stress fibers. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Cytoskeleton 07/2015; 72(6):n/a-n/a. DOI:10.1002/cm.21230 · 3.12 Impact Factor
    • "Cellularity of the aECM-coated scaffolds, as well as the proliferation and rate of matrix synthesis of dFbs, also do not indicate a spontaneous activation of dFbs that could result in unwanted overgrowth and fibrotic response around the biomaterials. To analyse the response to TGFβ1, a key modulator of dFbs during wound healing (Desmouliere et al., 1993; Hinz, 2007), we stimulated dFbs cultured in aECM-coated PLGA scaffolds. In general, TGFβ1 induction was less effective in 3D scaffolds compared to monolayer cultures, which might be due to absorption of TGFβ1 at the scaffold and to a gradient of accessible TGFβ1 after its application to the surrounding growth medium. "
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    ABSTRACT: Surface modification of materials designed for regenerative medicine may improve biocompatibility and functionality. The application of glycosaminoglycans (GAGs) and chemically sulphated GAG derivatives is a promising approach for designing functional biomaterials, since GAGs interact with cell-derived growth factors and have been shown to support fibroblast growth in two-dimensional (2D) cultures. Here, coatings with artificial extracellular matrix (aECM), consisting of the structural protein collagen I and the GAG hyaluronan (HA) or sulphated HA derivatives, were investigated for their applicability in a three-dimensional (3D) system. As a model, macroporous poly(lactic-co-glycolic acid) (PLGA) scaffolds were homogeneously coated with aECM. The resulting scaffolds were characterized by compressive moduli of 0.9-1.2 MPa and pore sizes of 40-420 µm. Human dermal fibroblasts (dFbs) colonized these aECM-coated PLGA scaffolds to a depth of 400 µm within 14 days. In aECM-coated scaffolds, collagen I(α1) and collagen III(α1) mRNA expression was reduced, while matrix metalloproteinase-1 (MMP-1) mRNA expression was increased within 7 days, suggesting matrix-degradation processes. Stimulation with TGFβ1 generally increased cell density and collagen synthesis, demonstrating the efficiency of bioactive molecules in this 3D model. Thus, aECM with sulphated HA may modulate the effectivity of TGFβ1-induced collagen I(α1) expression, as demonstrated previously in 2D systems. Overall, the tested aECM with modified HA is also a suitable material for fibroblast growth under 3D conditions. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 05/2015; DOI:10.1002/term.2037 · 5.20 Impact Factor
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