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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    • "known to trigger a classical foreign body response and leads to a chronic inflammation[66]driven by monocytes and macrophages recruited by chemokines and chemo attractants such as transforming growth factor-b (TGF-b), plateletderived growth factor (PDGF), and interleukin (IL-1). After chronic inflammation is resolved, fibroblast cells activate and differentiate into myofibroblasts due to the stimulation of TGF-b, a key regulator of extracellular matrix formation and remodeling[67]. Fibroblasts and myofibroblasts secrete collagen types I and III to form a fibrous capsule around the implant and contract the wound edges. Several studies demonstrated that TGF-b-inducible genes, including collagen and smooth muscle actin are suppressed by HDAC inhibitors[68,69]and the extracellular matrix remodeling is regulated by the inhibition of class I HDAC3[70]Moreover, also the process of collagen assembly or fibrillogenesis has been demonstrated to be affected by HDAC inhibitors[71]. "
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    ABSTRACT: Among epigenetic enzymes, histone deacetylases (HDACs) are responsible for regulating the expression of an extensive array of genes by reversible deacetylation of nuclear histones as well as a large number of non-histone proteins. Initially proposed for cancer therapy, recently the interest for HDAC inhibitors (HDACi) as orally active, safe, and anti-inflammatory agents is rising due to their ability in reducing the severity of inflammatory and autoimmune diseases. In particular, selective HDAC3, HDAC6, and HDAC8 inhibitors have been described to downregulate the expression of pro-inflammatory cytokines (TNF-α, TGF-β, IL-1β, and IL-6). Herein, using KB31, C2C12, and 3T3-J2 cell lines, we demonstrated that, under lipopolysaccharide-induced in vitro inflammation, HDAC3/6/8 inhibitor MC2625 and HDAC6-selective inhibitor MC2780 were effective at a concentration of 30 ng/mL to downregulate mRNA expression of pro-inflammatory cytokines (IL-1β and IL-6) and to promote the transcription of IL-10 gene, without affecting the cell viability. Afterwards, we investigated by immunohistochemistry the activity of MC2625 and MC2780 at a concentration of 60 ng/kg animal weight to regulate silicone-triggered immune response in C57BL/6J female mice. Our findings evidenced the ability of such inhibitors to reduce host inflammation in silicone implants promoting a thickness reduction of peri-implant fibrous capsule, upregulating IL-10 expression, and reducing the production of both IL-1β and IL-6. These results underline the potential application of MC2625 and MC2780 in inflammation-related diseases.
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    • "However, this property can also play a detrimental role in pathological processes. For example, excessive fibrotic growth can cause further damage to organs and carcinomaassociated fibroblasts derived from hMSCs can sustain cancer progression [5] [6] [7] [8] [9] [10] [11] [12]. Therefore, it is of importance to understand the underlying mechanisms driving hBMSCs to adopt a myofibroblast-like phenotype. "
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    ABSTRACT: Human bone marrow-derived stromal cells (hBMSCs) derived from the adult organism hold great promise for diverse settings in regenerative medicine. Therefore a more complete understanding of hBMSC biology to fully exploit the cells’ potential for clinical settings is important. The protein CD24 has been reported to be involved in a diverse range of processes such as cancer, adaptive immunity, inflammation, and autoimmune diseases in other cell types. Its expression in hBMSCs, which has not yet been analyzed, may add an important aspect in the understanding of hBMSC biology. The present study therefore analyzes the expression, regulation, and functional implication of the surface protein CD24 in hBMSCs. Methods used are stimulation studies with TGF beta as well as shRNA-mediated knockdown and overexpression of CD24 followed by microarray, immunocytochemistry, and flow cytometric analyses. To our knowledge, we demonstrate for the first time that the expression of CD24 is an inherent property of hBMSCs. Importantly, the data links the upregulation of CD24 to the adoption of a myofibroblast-like gene expression pattern in hBMSCs. We demonstrate that CD24 is an important modulator in transforming growth factor beta 3 (TGF β 3) signaling with a reciprocal regulatory relationship between these two proteins.
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    • "Myofibroblasts play a key role in tissue remodeling and wound healing [1] [2]. Being able to generate high traction forces and secrete abundant extracellular matrix (ECM) proteins, myofibroblasts can reorganize their surrounding matrix, rapidly close wounds and repair matrix damage [3]. "
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    ABSTRACT: Statement of significance: Myofibroblasts play an important role in tissue remodeling and wound healing. However, excessive activation of this phenotype is associated with fibrotic diseases and scar formation. Being able to dedifferentiate these cells or controlling their clearance with apoptosis (programmed cell death) would be beneficial. It is known that releasing rigid tissue boundaries trigger apoptosis, while reducing the substrate stiffness can cause myofibroblast dedifferentiation. However, the mechanical tension was not quantified in any of the studies. Here we used micro-cantilever posts at tissue boundaries to measure tension and to regulate boundary stiffness in real time by pulling posts with magnets. We show that temporary stiffening of boundary causes irreversible myofibroblast activation and the magnitude of tension drop controls apoptosis.
    No preview · Article · Dec 2015 · Acta biomaterialia
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