Force generation and transmission in keloid fibroblasts: dissecting the role of mechanosensitive molecules in cell function

Abstract

Wound healing is a complex multistep process that involves a number of different cell types and requires tight regulation of biochemical and biomechanical signalling (1). Fibroblasts are required to deposit and remodel extracellular matrix (ECM) within the wound to provide mechanical stability and a protein scaffold for other cells and growth factors. This is achieved by their concerted migration to the site of injury initiated by chemoattractants that are secreted as a consequence of an inflammatory response. At the wound site, they are activated to convert into myofibroblasts that are able to exert strong forces to the underlying ECM resulting in its rearrangement and remodelling (1) (Fig. 1a).Importantly, fibroblast activation and the resulting matrix production need to be transient and reversible. Failure to terminate these processes leads to formation of keloids that are characterized by a thickened epidermis, increased number of mesenchymal cells as well as increased vascularization (2). Although the molecular mechanisms of keloid formation are not completely clear, keloid fibroblasts (KF) are assumed to play a critical role in the pathogenesis. KFs differ from normal fibroblasts in terms of production of cytokines and ECM components (2). However, their mechanical properties, which could influence the characteristic migratory properties as well as the ability to remodel the ECM (3), have not been addressed so far. Recently, Harn and co-workers have investigated the mechanical properties of KFs and the underlying changes in the cytoskeleton of these cells (4).Harn and co-workers discover that KFs bear a characteristic elastic behaviour that is mainly dominated by the actin cytoskeleton. Interestingly, filament elasticity of KFs displays a biphasic distribution. Areas of high and low elasticity are interpreted as assembling and disassembling focal adhesion sites, respectively. The authors show that coupling of mechanical forces of KFs to the ECM differs from normal fibroblasts in terms of strength and spatial distribution (4). The increased migratory behaviour of KFs is accompanied by an increased net force exerted to the substrate facilitating cellular movement via a mesenchymal-like mode of migration (Fig. 1b).We agree with the authors that the elastic behaviour of actin filaments is likely to mirror the magnitude of the force loaded on the filaments and the matrix and therefore influences cellular locomotion. We and others have observed similar behaviour in fibroblasts deficient in the integrin adaptor, integrin-linked kinase (ILK). These cells are unable to establish a stable link between ECM-bound integrins and the actin cytoskeleton and therefore display a disorganized actin cytoskeleton, a decline in traction force and a concomitant lower migration rate as well as a severe impairment in ECM remodelling (5). This highlights the importance of proper force transmission from the actin cytoskeleton to the ECM in fibroblast function.In line with this, Harn et al. (4) observed that inhibiting the activity of...

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

“…The functional association between NRG1 and ErbB2 on cell migration has been observed in cardiac myocytes, Schwann cells and glioma tissue, indicating the NRG-1β/ ErbB-dependent activation of Src/FAK modulates cellcell contact, cell motility and focal adhesion complex formation (20,22). Indeed protein tyrosine kinase 2 (PTK2/ FAK), a non-receptor protein tyrosine kinase, was shown to be upregulated in keloid disease, where it influences cell migration through alteration of the focal-complex assembly disassembly cycle (23)(24)(25). The aggressive invasion evident in keloid disease supports the hypothesis of a mechanobiological aetiology (26,27), where rapid focal adhesion turnover and modulation of tension actin filaments produce a "migration-related disease" (28).…”

The Aldo-Keto Reductase AKR1B10 Is Up-Regulated in Keloid Epidermis, Implicating Retinoic Acid Pathway Dysregulation in the Pathogenesis of Keloid Disease

“…Here, in an innovative approach to KD, we have combined LCM and whole-genome microarray to isolate separate in situ gene profiles of KE and keloid dermis for selected keloid sites and compared these with normal skin. Traditionally, the bulk of KD research has focused on the dermis, where fibroblasts are considered the culprits of pathological extracellular matrix deposition (Dohi et al, 2015;Kashiyama et al, 2012;Schneider and Wickstrom, 2015). Therefore, despite the facts that the epidermis is invariably the first layer affected by the trauma that initiates keloid formation and that epidermal injury may well be a condition sine qua non for KD development, comparatively few studies have focused on the role of the epidermis and implications for epithelial-mesenchymal interactions in keloid pathogenesis (Hahn et al, 2013;Yan et al, 2015).…”

Is early inflammation good or bad? Linking early immune changes to hypertrophic scarring

“…Directly correlating reduced and/or delayed very early inflammatory responses to later HTS formation also suffers from lack of taking other important factors that may have contributed to the development of HTS into consideration. Influence of mechanical forces on cellular fibrotic responses during the course of healing has long been emphasized by us and other investigators . Recent evidence from our own studies shows that mechanical stimuli can prolong acute inflammation via activation of the cellular mechanotransduction pathways, eventually leading to fibrotic mechanisms …”

“…Influence of mechanical forces on cellular fibrotic responses during the course of healing has long been emphasized by us and other investigators. 6,7 Recent evidence from our own studies shows that mechanical stimuli can prolong acute inflammation via activation of the cellular mechanotransduction pathways, eventually leading to fibrotic mechanisms. 6 Results of this current study may seemingly coincide with previous findings from others showing that development of HTS and fibrosis is not always characterized by prolonged inflammation.…”