Wound Mechanotransduction in Repair and Regeneration Victor W

REVIEW Pushing Back: Wound Mechanotransduction in Repair and Regeneration Victor W. Wong1, Satoshi Akaishi1, Michael T. Longaker1 and Geoffrey C. Gurtner1 Human skin is a highly specialized mechanorespon- These physical interactions regulate key developmental and sive interface separating our bodies from the external homeostatic mechanisms and underlie the tremendous environment. It must constantly adapt to dynamic functional plasticity of skin (Silver et al., 2003; Blanpain physical cues ranging from rapid expansion during and Fuchs, 2009). Although mechanical forces are implicated embryonic and early postnatal development to ubi- in the pathogenesis of numerous diseases (Ingber, 2003a), quitous external forces throughout life. Despite the their role in cutaneous biology remains poorly understood. suspected role of the physical environment in However, the fundamental mechanisms responsible for cutaneous processes, the fundamental molecular mechanotransduction (the conversion of physical stimuli into mechanisms responsible for how skin responds to biochemical responses) are increasingly being elucidated on force remain unclear. Intracellular pathways convert molecular and cellular levels (Ingber, 2006). The ongoing challenge for researchers and clinicians is to fully understand mechanical cues into biochemical responses (in a these mechanotransduction pathways in living organs so that process known as mechanotransduction) via complex they can be translated into clinical therapies. mechanoresponsive elements that often blur the In 1861, the German anatomist Karl Langer published the distinction between physical and chemical signaling. observation that skin exhibits intrinsic tension (Langer K, For example, cellular focal adhesion components 1978), a finding he attributed to the French surgeon Baron exhibit dual biochemical and scaffolding functions Guillaume Dupuytren. Since then, surgeons have adhered to that are critically modulated by force. Moreover, the the concept of ‘‘Langer’s lines,’’ which are topographical skin extracellular matrix itself is increasingly recognized to lines defined by the direction in which the circular wounds mechanically regulate the spatiotemporal distribution will elongate (becoming ellipsoid) in different anatomic regions of soluble and matrix-bound ligands, underscoring of the body. Subsequent studies have defined numerous other the importance of bidirectional crosstalk between topographical line maps throughout the body using differ- cells and their physical environment. It seems likely ent biomechanical methodologies (Wilhelmi et al., 1999). that a structural hierarchy exists to maintain both cells Regardless, the common underlying theory is that incisions and matrix in mechanical homeostasis and that made across these imaginary lines are exposed to greater dysregulation of this architectural integrity may tension (from the orientation of collagen fibers or contraction underlie or contribute to various skin disorders. An of underlying muscles) and form quantitatively more scar improved understanding of these interactions will tissue. This phenomenon is substantiated clinically as facilitate the development of novel biophysical wounds in high-mechanical-stress regions (such as the materials and mechanomodulatory approaches to sternum and shoulder) have been shown to be prone to augment wound repair and regeneration. exuberant fibrosis (Ogawa, 2008). From the simplest single-celled organism to the most Journal of Investigative Dermatology advance online publication, 21 July 2011; doi:10.1038/jid.2011.212 complex of mammals, all living systems are in constant interaction with the physical world. This ability to precisely sense and respond to mechanical cues has been retained throughout evolution and is embodied in humans as the INTRODUCTION integumentary system. As such, it is becoming increasingly Human skin constantly senses and adapts to a wide range clear that the mechanical environment has significant effects of mechanical cues that are ubiquitous throughout life. on cutaneous biology and may have wide pathogenic relevance. This review will focus in particular on the role of mechanical force in wound repair and explore previously 1Department of Surgery, Stanford University School of Medicine, Stanford, unreported therapeutic approaches to mechanically control California, USA wound biology and phenotype. Correspondence: GC Gurtner, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, California 94305, USA. E-mail: [email protected] INTRACELLULAR MECHANOTRANSDUCTION Abbreviations: ECM, extracellular matrix; NPWT, negative pressure wound There are several major interrelated pathways by which therapy cells are mechanically stimulated, including integrin–matrix Received 8 April 2011; revised 25 May 2011; accepted 27 May 2011 interactions, cytoskeletal strain, and stretch ion channels & 2011 The Society for Investigative Dermatology www.jidonline.org 1 VW Wong et al. Wound Mechanotransduction in Repair and Regeneration Extracellular matrix Mechanical forces Stretch- Growth factor activated receptors Integrins G-protein-coupled ion channels receptors FAK Plasma membrane Cytosol Ca2+ NO MAPK Rho PI3K Actin Transcription factors cytoskeleton Mechanoresponsive genes Nucleus Figure 1. Intracellular mechanisms of mechanotransduction. Mechanical force is sensed by the integumentary system and activates multiple intracellular signaling pathways. Several membrane-bound mechanosensory complexes have been described and include stretch-activated ion channels, growth factor receptors, integrins, and G-protein-coupled receptors. Of primary significance in fibroblasts and keratinocytes is matrix–integrin activation of focal adhesion complexes that contain focal adhesion kinase (FAK). Mechanical force is transmitted across the cell membrane to activate downstream biochemical pathways including but not limited to calcium-dependent targets, nitric oxide (NO) signaling, mitogen-associated protein kinases (MAPKs), Rho GTPases, and phosphoinositol-3-kinase (PI3K). The convergence of these signals results in the activation of transcription factors that translocate to the nucleus and activate mechanoresponsive genes (adapted from Jaalouk and Lammerding, 2009). (Figure 1). Cells bind to the extracellular matrix (ECM) Although the precise mechanisms are only beginning to be through transmembrane integrins that associate with various elucidated, it has been demonstrated that cells can distin- binding proteins and kinases (e.g., focal adhesion kinase) to guish subtle temporal differences in mechanical stimulation trigger downstream targets such as the family of mitogen- and adaptively strengthen their adhesion structures activated protein kinases, GTPases, active oxygen species, (Matthews et al., 2006). Biosensor components implicated and cytoskeletal elements (Katsumi et al., 2004; Jaalouk and in this process include focal adhesion complexes, the Rho Lammerding, 2009). These integrin-associated proteins GTPase family of signaling molecules, and mechanosensitive (known as focal adhesion complexes) also link to the actin ion channels. Rho signaling pathways, intimately involved in cytoskeleton via adaptor proteins (e.g., talin, paxillin, cytoskeletal dynamics, are also known to regulate fibroblast vinculin) and directly modulate cell behavior such as motility and keratinocyte responses to mechanical force (Harvey and proliferation (Alenghat and Ingber, 2002). In addition, et al., 2007; Reichelt, 2007), highlighting the important mechanosensitive stretch ion channels control calcium- functional relationship between cell shape and behavior in dependent pathways that further regulate intracellular signal- skin cells. ing and cytoskeletal remodeling (Silver et al., 2003; Lumpkin Consistent with this paradigm, complex organs such as and Caterina, 2007). It is important to note that many of these skin also exhibit tensegrity, and their response to physical networks are also regulated by growth factor and G-protein- stimuli may similarly function to restore biomechanical coupled receptor pathways (Jaalouk and Lammerding, 2009), equilibrium (Silver et al., 2003; Ingber, 2008). This hierarchi- which can potentially be transactivated by mechanical force cal organization is likely to be of major relevance following in a ligand-independent manner (Knies et al., 2006), further cutaneous injury when skin architecture is extensively illustrating the complex intricacies of cellular mechanotrans- disrupted and the mechanical context of its constituent cells duction and intracellular signaling. is dramatically altered. Current research supports the concept Despite this complexity, a unifying concept known as that these mechanotransduction events play a critical role in ‘‘tensegrity’’ has been proposed to describe how mechanical the response to injury and may underlie the etiology of force regulates biological systems via perturbations in fibroproliferative skin diseases (Aarabi et al., 2007a; Gurtner structural architecture (Figure 2) (Ingber, 2003b, c). Altera- et al., 2011). tions in the physical microenvironment can disrupt this Another important concept is that cells not only passively tensional integrity, thus triggering broad intra- and inter- respond to force but also actively generate intracellular cellular pathways to reestablish mechanical homeostasis tension as they probe their local environment, the so-called (Eckes and Krieg, 2004). Structural components linking the cell traction

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