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Skin development and regeneration, and the control of fibrosis
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
Michael S. Hu, H. Peter Lorenz, Michael T. Longaker
As the proliferation stage of wound healing begins, macrophages adopt a profibrotic, anti-inflammatory phenotype. In so doing, they secrete growth factors such as transforming growth factor (TGF)-beta, recruiting fibroblasts into the wound (Baum and Arpey 2005). In turn, endothelial cells are stimulated into the wound by factors such as vascular endothelial growth factor (VEGF) and undergo angiogenesis (Bao et al. 2009). Keratinocytes from the wound edges and hair follicle bulge regions continue to migrate, proliferate, and differentiate to complete re-epithelialization (Raja et al. 2007). Although stem cells are involved in the wound repair process, epidermal appendages are not regenerated (Baum and Arpey 2005). Extracellular matrix components such as fibronectin and cytokines such as TGF-β stimulate fibroblast activation into myofibroblasts (Wynn and Ramalingam 2012; Gabbiani 2003). These activated fibroblasts, named by their contractile ability due to the expression of alpha-smooth muscle actin (SMA), physically pull the edges of the wound together, decreasing the wound size (Gurtner et al. 2008). Although myofibroblasts play this desired role in wound healing, they are also responsible for the secretion of abnormal ECM, composed of increased levels of immature type III collagen, characteristic of scar tissue (Duffield et al. 2013).
In vitro modulatory effects of electrical field on fibroblasts
Published in Ze Zhang, Mahmoud Rouabhia, Simon E. Moulton, Conductive Polymers, 2018
Fibroblasts are a key player in epithelium restoration after injury. In a normal wound healing process, fibroblasts directly or indirectly, through mediators, play key roles in inflammation, the formation of granulation tissue, tissue reepithelialization, and remodeling. Involved in the wound healing process, fibroblasts change phenotypes to myofibroblasts expressing alpha-smooth muscle actin (α-SMA), an early differentiation marker of smooth muscle cells (Hinz and Gabbiani 2003). Myofibroblasts are found in the early phase of granulation tissue formation (Marangoni et al. 2015), become most abundant during the proliferation phase of wound healing, and gradually disappear during the remodeling phase, presumably through an apoptotic process (Ross et al. 1970). However, scars can occur during wound healing. In nonhealing wounds, fibroblasts become dysfunctional, producing less much-needed growth factors, including bFGF (Akita et al. 2013), PDGF (Demaria et al. 2014), and VEGF (Bao et al. 2009). This suggests possible clinical strategies that include modulating one or multiple mediators to restore the wound healing process. However, this may not be possible without restoring the normal function of fibroblasts and keratinocytes. Thus, there still a critical need for new strategies to manage nonhealing wounds, such as diabetic foot ulcers, pressure ulcers, and chronic venous ulcers, which represent a major healthcare burden all over the world. Stimulating cells, including fibroblasts, during the wound healing process could be a valuable way to restore cell functions and contribute to the clinical management of nonhealing wounds.
Cell and Extracellular Matrix Interactions in a Dynamic Biomechanical Environment:
Published in Michel R. Labrosse, Cardiovascular Mechanics, 2018
Myofibroblasts are traditionally identified as an intermediate cell type between fibroblasts and SMCs, with characteristic upregulated α-smooth muscle actin (αSMA). They form stress fibers and vimentin, but lack the desmin, heavy-chain smooth muscle myosin, and smoothelin of SMCs (Darby et al. 2014). Myofibroblasts have been found to differentiate from a variety of cell types, most commonly fibroblasts, but also mesenchymal stem cells (MSCs), SMCs, and endothelial cells after endothelial-to-mesenchymal transition among others (Hinz et al. 2007, Barisic-Dujmovic et al. 2010). Transforming growth factor β1 is a key regulator of myofibrogenesis by controlling αSMA expression (Desmouliere et al. 1993). Myofibroblasts have upregulated ECM synthesis, producing disorganized collagen and fibronectin in large amounts (Gabbiani et al. 1971, Torr et al. 2015), which when combined with upregulated MMP activity (Rabkin et al. 2001) means that myofibroblasts can remodel the ECM in a disruptive and disorganized manner. Myofibroblasts are also highly contractile due the presence of contractile bundles of actin and myosin (Hinz 2010). Upregulated ECM synthesis and contractility make myofibroblasts useful for wound healing, where they can rapidly close and stabilize the wound, but they are not capable of true regeneration, since original tissue function is not restored. On resolution of injury, recruited myofibroblasts should disappear via apoptosis (Desmouliere et al. 1995), while the continued presence of unregulated myofibroblasts leads to fibrosis. Similarly, the presence of low levels of myofibroblasts in the valve assists in valve homeostasis, but increased myofibrogenesis leads to valve disease (discussed in detail in Section 2.3).
Protective effects of natural compounds against paraquat-induced pulmonary toxicity: the role of the Nrf2/ARE signaling pathway
Published in International Journal of Environmental Health Research, 2023
Hasan Badibostan, Nastaran Eizadi-Mood, A. Wallace Hayes, Gholamreza Karimi
Resveratrol (Res) is a phytoalexin polyphenol that is found in a variety of plants (Neumann et al. 2009). Res has anticancer, antiobesity, and cardioprotective properties (Alamolhodaei et al. 2017; Tabeshpour et al. 2018; Ahmadi et al. 2021). Under the stimulation of pro-fibrogenic elements such as PQ, myofibroblasts are activated. Alpha smooth muscle actin (αSMA) is generated during myofibroblast activation (Tang et al. 2014; Staloch et al. 2015; Xie et al. 2016). Extensive disruption of cell-cell contact can stimulate (TGF)-β1-induced epithelial-mesenchymal transition (EMT) and the myofibroblast marker αSMA (O’Connor et al. 2016; Zhuang et al. 2019). Neumann and co-workers showed that PQ induced the generation of αSMA, TGF β1, and inflammatory cytokines in BEAS- 2B cells (Neumann et al. 2009). It was observed that Res inhibited the fibrogenic response and oxidative damage resulting from PQ exposure in these cells. In comparison to cells treated with PQ, TNF-α, IL-6, TGF β1, αSMA, and collagen I levels were significantly lower in cells also treated with Res (Neumann et al. 2009). A similar result was reported by He and co-workers (He et al. 2012). They showed that Res can inhibit the effect of PQ on inflammatory and profibrogenic factors (He et al. 2012).
Low-dose cadmium exposure exacerbates polyhexamethylene guanidine-induced lung fibrosis in mice
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Min-Seok Kim, Sung-Hwan Kim, Doin Jeon, Hyeon-Young Kim, Jin-Young Han, Bumseok Kim, Kyuhong Lee
Extracellular matrix (ECM) is a highly dynamic structural network that is present in all tissues and continuously undergoes balanced remodeling (Bonnans, Chou, and Werb 2015). Remodeling of the ECM by myofibroblasts is important for wound healing; however, dysregulation of ECM remodeling leads to pathological fibrosis (Bonnans, Chou, and Werb 2015; Minton 2014). Multiple mechanisms and mediators contribute to ECM alterations in IPF. MMPs are important regulators of ECM and regulate cytokines, growth factors, ECM deposition, and tissue reorganization (Madala et al. 2010; Wynn 2007). TGF-β1 is a key inducer of epithelial–mesenchymal transition and mediator of pulmonary fibrosis (Border and Noble 1994; Kasai et al. 2005; Li et al. 2016; Luo et al. 2016). Fibronectin is an ECM component. Fibronectin levels increase during tissue repair; however, excessive fibronectin accumulation leading to fibrosis. In the present study, expression of MMP12, TGF-β1, and fibronectin was elevated in pulmonary tissues of mice in the PHMG + CdCl2 compared to PHMG alone (Figure 6). Further, alterations in expression of fibrogenic mediators were consistent with changes in the expression of inflammatory cytokines. Inflammatory cytokines drive the progression of fibrosis in injured tissues by regulating the production of fibrogenic mediators (Borthwick, Wynn, and Fisher 2013). For example, IL-1β is a potent inducer of TGF-β1 and MMP production by various connective tissue cells (Wright, Cawston, and Hazleman 1991; Yue et al. 1994). Therefore, increased expression of these fibrogenic mediators may be attributed to Cd-induced inflammatory responses. In addition, Cd may induce fibrosis through inflammation-independent fibrotic mechanisms. Recently, Hu et al. (2017) noted that exposure to low Cd level stimulates pulmonary fibrotic signaling and myofibroblast differentiation. Li et al. (2017) found that Cd exposure stimulated vimentin phosphorylation and Yes-associated protein 1 (YAP1) activation, leading to peribronchiolar fibrosis and subsequent airway remodeling. However, further studies are needed to completely elucidate the influence of Cd in induction of pulmonary fibrosis.