The repair of injured tissue must occur rapidly to prevent microbial invasion and maintain tissue integrity. Epithelial tissues in particular, which serve as a barrier against the external environment, must repair efficiently in order to restore their primary function. Here we analyze the effect of different parameters on the epithelial wound repair process in the late stage Drosophila embryo using in vivo wound assays, expression of cytoskeleton and membrane markers, and mutant analysis. We define four distinct phases in the repair process-expansion, coalescence, contraction, and closure-and describe the molecular dynamics of each phase. Specifically, we find that myosin, E-cadherin, Echinoid, the plasma membrane, microtubules, and the Cdc42 small GTPase respond dynamically during wound repair, and demonstrate that perturbations of each of these components result in specific impairments to the wound healing process. Our results show that embryonic epithelial wound repair is mediated by two simultaneously acting mechanisms: crawling driven by cellular protrusions and actomyosin ring contraction along the leading edge of the wound.
"Damaged cells are able to restore the plasmalemma barrier function through addition of membrane material to the plasmalemma surface, dynamic changes in the shape of the plasmalemma  and by restoring normal cytoskeletal structures (e.g., via the formation of an actomyosin purse-string      ). As such, in addition to restoring the barrier function of the cell membrane, single cell wound healing can also be viewed as an attempt at restoring tensegrity to the wounded cell. "
"It has been suggested in other systems that a purse string is a common mechanism by which epithelial closure takes place during both development  and repair , . Our system excludes this possibility due to the geometry of the tubule. "
[Show abstract][Hide abstract] ABSTRACT: Acute kidney injury (AKI) is a common and significant medical problem. Despite the kidney's remarkable regenerative capacity, the mortality rate for the AKI patients is high. Thus, there remains a need to better understand the cellular mechanisms of nephron repair in order to develop new strategies that would enhance the intrinsic ability of kidney tissue to regenerate. Here, using a novel, laser ablation-based, zebrafish model of AKI, we show that collective migration of kidney epithelial cells is a primary early response to acute injury. We also show that cell proliferation is a late response of regenerating kidney epithelia that follows cell migration during kidney repair. We propose a computational model that predicts this temporal relationship and suggests that cell stretch is a mechanical link between migration and proliferation, and present experimental evidence in support of this hypothesis. Overall, this study advances our understanding of kidney repair mechanisms by highlighting a primary role for collective cell migration, laying a foundation for new approaches to treatment of AKI.
PLoS ONE 07/2014; 9(7):e101304. DOI:10.1371/journal.pone.0101304 · 3.23 Impact Factor
"The assembly of the actin ring requires the coordination of the cytoskeleton across the membranes of the epithelial cells surrounding the wound edge. Because Src42A has been implicated in the control of E-cadherin trafficking, it is tempting to speculate that its role in re-epithelialization is to control the adhesion of the leading cells, thereby controlling wound constriction (Abreu-Blanco et al., 2012; Förster and Luschnig, 2012; Nelson et al., 2012). By contrast, Btk29A and Src64B control the growth of the actin-rich ovarian ring canals (Lu et al., 2004) and microfilament contraction during cellularization (Thomas and Wieschaus, 2004), suggesting that they might preferentially control actin-filament assembly and contraction at the wound edge. "
[Show abstract][Hide abstract] ABSTRACT: Metazoans have evolved efficient mechanisms for epidermal repair and survival upon injury. Several cellular responses and key signaling molecules involved in wound healing have been identified in Drosophila but the coordination of cytoskeletal rearrangements and the activation of gene expression during barrier repair is poorly understood. The Ret-like, receptor tyrosine kinase Stitcher (Stit) regulates both re-epithelialization and transcriptional activation by Grainy head (Grh) to induce extracellular barrier restoration. Here, we describe the immediate down-stream effectors of Stit signaling in vivo. Drk (downstream of receptor kinase) and Src-family tyrosine kinases bind to the same docking site in the Stit intracellular domain. Drk is required for the full activation of transcriptional responses but is dispensable for re-epithelialization. By contrast, Src-family kinases control both the assembly of a contractile actin ring at the wound periphery and Grh-dependent activation of barrier repair genes. Our analysis identifies distinct pathways mediating injury responses and reveals an RTK-dependent activation mode of Src-kinases and their central functions during epidermal wound healing in vivo.
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