Cutaneous wound healing is a complex process involving numerous cell types to accomplish sequential, yet overlapping phases of inflammation, proliferation and tissue remodelling. 1,2 Immediately after injury, blood components are released into the wound, forming a clot which provides a matrix for the influx of inflammatory cells.The inflammatory phase is characterized by leukocyte migration to the wound. Neutrophils primarily remove bacteria, followed by monocytes which further differentiate into macrophages that exert early pro-inflammatory and late anti-inflammatory functions during the healing process. Deposition of the newly synthesized fibrin matrix and granulation tissue formation follow; these are subsequently replaced by collagen and scar tissue during the final stages of wound healing. The proliferative phase of wound healing is characterized by re-epithelialization, neovascularization and extracellular matrix deposition. 1,3 Historically, exploration of the molecular basis of wound healing has included a primary focus on its spatiotemporal regulation. Given the complexity of the wound healing process and its requirement for stringent regulation, epigenetic regulation including histone modifications and DNA methylation is highly likely to play a role. 4,5 Indeed, recent discoveries in the field of non-coding RNAs have identified roles for microRNAs (miRs), circular RNAs (circRNA) and long noncoding RNAs (lncRNA) as global gene expression regulators involved in an array of processes important for successful wound healing. [6][7][8][9] While the primary focus of previous reviews has been on the role of epigenetic modifications in acute wound healing, 4-8 herein we
Although impaired keratinocyte migration is a recognized hallmark of chronic wounds, the molecular mechanisms underpinning impaired cell movement are poorly understood. Here, we demonstrate that both diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) exhibit global deregulation of cytoskeletal organization in genomic comparison to normal skin and acute wounds. Interestingly, we found that DFUs and VLUs exhibited downregulation of ArhGAP35, which serves both as an inactivator of RhoA and as a glucocorticoid repressor. Since chronic wounds exhibit elevated levels of cortisol and caveolin-1 (Cav1), we posited that observed elevation of Cav1 expression may contribute to impaired actin-cytoskeletal signaling, manifesting in aberrant keratinocyte migration. We showed that Cav1 indeed antagonizes ArhGAP35, resulting in increased activation of RhoA and diminished activation of Cdc42, which can be rescued by Cav1 disruption. Furthermore, we demonstrate that both inducible keratinocyte specific Cav1 knockout mice, and MβCD treated diabetic mice, exhibit accelerated wound closure. Taken together, our findings provide a previously unreported mechanism by which Cav1-mediated cytoskeletal organization prevents wound closure in patients with chronic wounds.
Diabetic foot ulcers (DFUs) are a widespread and debilitating type of chronic wound disorder and the most frequent cause for diabetesrelated hospitalization prior to COVID-19. 1 Dermal fibroblasts are an important cell type involved in physiological wound healing, with the role in production and remodelling of extracellular matrix (ECM), granulation tissue formation, support of re-epithelialization and regulation of angiogenesis; however, all of these processes are found deregulated in DFUs. [2][3][4][5] We previously characterized primary fibroblasts from non-healing DFUs (DFUFs) and evaluated their properties in comparison with non-diabetic foot fibroblasts (NFFs) and diabetic foot fibroblasts (DFFs) on the phenotypic and mRNA expression level. 2,6,7 DFUFs were characterized with impaired cellular migration and proliferation, as well as dysregulated differentiation and induced senescence. 2,6 Furthermore, DFUFs
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