Soft tissue mechanotransduction in wound healing and fibrosis
Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine,USA. Seminars in Cell and Developmental Biology
(Impact Factor: 6.27).
10/2012; 23(9). DOI: 10.1016/j.semcdb.2012.09.010
Recent evidence suggests that mechanical forces can significantly impact the biologic response to injury. Integrated mechanical and chemical signaling networks have been discovered that enable physical cues to regulate disease processes such as pathologic scar formation. Distinct molecular mechanisms control how tensional forces influence wound healing and fibrosis. Conceptual frameworks to understand cutaneous repair have expanded beyond traditional cell-cytokine models to include dynamic interactions driven by mechanical force and the extracellular matrix. Strategies to manipulate these biomechanical signaling networks have tremendous therapeutic potential to reduce scar formation and promote skin regeneration.
Available from: Marcy Zenobi
- "During early wound healing, the provisional Fn-rich matrix is remodeled and later interlaced by type I collagen (Col1) and type III collagen (Reinke and Sorg, 2012), of which excessive bundling often leads to problematic fibrosis (Gabbiani, 2003; Shaw and Martin, 2009; Bryers et al., 2012) and excessive wound contracture (Montesano and Orci, 1988; da Rocha-Azevedo et al., 2013). Also mechanical forces acting on cells and tissues affect many physiological processes, from tissue development such as the assembly and remodeling of extracellular matrix (ECM) in connective tissue (Tomasek et al., 2002; Chiquet et al., 2009; Geiger et al., 2009; Cox and Erler, 2011; Dideriksen et al., 2013) to repair processes such as wound healing (Kippenberger et al., 2000; Gabbiani, 2003; Wong et al., 2011) and scar formation (Aarabi et al., 2007; Gurtner et al, 2008; Wong et al., 2012). "
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ABSTRACT: Early wound healing is associated with fibroblasts assembling a provisional fibronectin-rich extracellular matrix (ECM), which is subsequently remodeled and interlaced by type I collagen. This exposes fibroblasts to time-variant sets of matrices during different stages of wound healing. Our goal was thus to gain insight into the ECM-driven functional regulation of human foreskin fibroblasts (HFFs) being either anchored to a fibronectin (Fn) or to a collagen-decorated matrix, in the absence or presence of cyclic mechanical strain. While the cells reoriented in response to the onset of uniaxial cyclic strain, cells assembled exogenously added Fn with a preferential Fn-fiber alignment along their new orientation. Exposure of HFFs to exogenous Fn resulted in an increase in matrix metalloproteinase (MMP) expression levels, i.e. MMP-15 (RT-qPCR), and MMP-9 activity (zymography), while subsequent exposure to collagen slightly reduced MMP-15 expression and MMP-9 activity compared to Fn-exposure alone. Cyclic strain upregulated Fn fibrillogenesis and actin stress fiber formation, but had comparatively little effect on MMP activity. We thus propose that the appearance of collagen might start to steer HFFs towards homeostasis, as it decreased both MMP secretion and the tension of Fn matrix fibrils as assessed by Fluorescence Resonance Energy Transfer. These results suggest that HFFs might have a high ECM remodeling or repair capacity in contact with Fn alone (early event), which is reduced in the presence of Col1 (later event), thereby down-tuning HFF activity, a processes which would be required in a tissue repair process to finally reach tissue homeostasis.
Available from: Christopher Moraes
- "The ability for a cell to remodel the surrounding extracellular matrix (ECM) is a critical feature in development, homeostasis and disease progression. In particular, cell-mediated contraction of collagen matrices occurs in a variety of situations including embryo development [1e3], wound healing [4e7], and the formation of fibrotic scars and lesions . In vitro collagen contraction assays have provided important insights into biological processes, by enabling the production of tissue-like structures  that may serve as engineered replacements [10e13] or as model systems to investigate disease pathologies [14e17]. "
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ABSTRACT: This work describes the use of aqueous two-phase systems to print cell-containing contractile collagen microdroplets. The fully aqueous conditions enable convenient formation of sub-microliter 'microgels' that are much smaller than otherwise possible to fabricate while maintaining high cell viability. The produced microgels contract over several days, mimicking the behavior of macroscale contraction assays, which have been valued as an important biological readout for over three decades. Use of microgels not only reduces reagent consumption and increases throughput of the assay, but also improves transport of molecules into and out of the collagen matrix, thereby enabling efficient and more precise studies of timed stimulation profiles. Utility of the technology is demonstrated by analyzing the effects of TGF-β1 on gel contraction, and we demonstrate that brief 'burst' stimulation profiles in microgels prompt contraction of the matrix, a feature not observed in the conventional macroscale assay. The fully aqueous process also enables the integration of contractile collagen microgels within existing cell culture systems, and we demonstrate proof-of-principle experiments in which a contractile collagen droplet is fabricated in situ on an existing epithelial monolayer. The simplicity, versatility and ability to robustly produce collagen microgels should allow effective translation of this microengineering technology into a variety of research environments.
Available from: Xiaojin Liu
- "Fibroblast contraction requires participation of ECM, focal adhesion and cytoskeleton , while integrins are the core of focal adhesion, which mediate the connection between ECM and cytoskeleton , . Integrin α1 and α2 are two highly expressed integrins in fibroblasts that recognize collagen . "
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ABSTRACT: Lumican is a dermatan sulfate proteoglycan highly expressed in connective tissue and has the ability to regulate collagen fibril assembly. Previous studies have shown that lumican is involved in wound healing, but the precise effects of lumican on reepithelialization and wound contraction, the two pivotal aspects of skin wound healing, have not been investigated. Here we explored the roles of lumican in fibroblast contractility, a main aspect of skin wound healing, by adopting mice skin wound healing model and the corresponding in vitro cellular experiments. Our results showed that lumican can promote skin wound healing by facilitating wound fibroblast activation and contraction but not by promoting keratinocyte proliferation and migration. Silencing of integrin α2 completely abolished the pro-contractility of lumican, indicating lumican enhances fibroblast contractility via integrin α2. Our study for the first time demonstrated that lumican can affect fibroblast's mechanical property, which is pivotal for many important pathological processes, such as wound healing, fibrosis, and tumor development, suggesting that lumican might have a potential to be used to modulate these processes.
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