Abstract
Impaired wound healing and tissue regeneration have severe consequences on the patient's quality of life. Micrograft therapies are emerging as promising and affordable alternatives to improve skin regeneration by enhancing the endogenous wound repair processes. However, the molecular mechanisms underpinning the beneficial effects of the micrograft treatments remain largely unknown. In this study, we identified the active protein-1 (AP-1) member Fos-related antigen-1 (Fra-1) to play a central role in the extracellular signal-regulated kinase- (ERK-) mediated enhanced cell migratory capacity of soluble micrograft-treated mouse adult fibroblasts and in the human keratinocyte cell model. Accordingly, we show that increased micrograft-dependent in vitro cell migration and matrix metalloprotease activity is abolished upon inhibition of AP-1. Furthermore, soluble micrograft treatment leads to increased expression and posttranslational phosphorylation of Fra-1 and c-Jun, resulting in the upregulation of wound healing-associated genes mainly involved in the regulation of cell migration. Collectively, our work provides insights into the molecular mechanisms behind the cell-free micrograft treatment, which might contribute to future advances in wound repair therapies.
Highlights
The skin is the largest organ of the human body providing protection, immune defense, and sensation
A recent study indicated that increased autologous micrograft- (AMG-) mediated fibroblast migration requires activation of the extracellular signal-regulated kinase (ERK) signaling pathway that has been shown to be induced by the growth factors present in the soluble fraction of the micrograft [19]
The initial transcriptome analysis showed 123 upregulated differentially expressed genes (DEGs), including genes involved in cell migration (i.e., Cxcl2, Ccl20, Mmp3), angiogenesis (i.e., Ets1, Vegfa, Flt1), cell cycle (i.e., Nos2, Ptgs2, Lif), and epithelialization (i.e., Dusp10, Ptgs2, Hmox1) (Figures 1(b) and 1(c), Table S2)
Summary
The skin is the largest organ of the human body providing protection, immune defense, and sensation. TGF-β signaling and the classical transcription factor NF-κB have been described as regulators which elicit the immune response as the initial step of the wound healing process This results in the immune cell and platelet-derived production of a plethora of growth factors including transforming growth factor-beta (TGF-β), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and connective tissue growth factor (CTGF) at the site of injury [4,5,6]. These in turn establish key repair processes such as angiogenesis, matrix deposition, migration, proliferation, and fibroblast transdifferentiation through pivotal signaling cascades [4]. The activator protein-1 (AP-1) family has been reported as a transcription factor downstream of the ERK
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