Enhanced Keratinocyte Migration Research Articles

Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing.

Skin wound healing involves a complex gene expression program that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process. To understand the functions and potential interactions of circRNAs and miRNAs in human skin wound healing. CircRNA, linear RNA, and miRNA expression in human acute and chronic wounds were analyzed using RNA sequencing and qRT-PCR. The roles of circASH1L(4,5) and miR-129-5p were studied in human primary keratinocytes (proliferation and migration assays, microarray analysis) and ex vivo wound models (histological analysis). The interaction between circASH1L(4,5) and miR-129-5p was examined using luciferase reporter and RNA pull-down assays. We identified circASH1L(4,5) and its interaction with miR-129-5p, both of which increased during human skin wound healing. Unlike typical miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting it from target-directed degradation triggered by NR6A1 mRNA. TGF-β signaling, crucial in wound healing, promoted circASH1L expression while suppressing NR6A1, thereby increasing miR-129 abundance at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds. Our study uncovers a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.

Immunomodulatory hydrogel orchestrates pro-regenerative response of macrophages and angiogenesis for chronic wound healing

Chronic wound healing often encounters challenges characterized by prolonged inflammation and impaired angiogenesis. While the immune response plays a pivotal role in orchestrating the intricate process of wound healing, excessive inflammation can hinder tissue repair. In this study, a bilayer alginate hydrogel system encapsulating polyelectrolyte complex nanoparticles (PCNs) loaded with anti-inflammatory cytokines and angiogenic growth factors is developed to address the challenges of chronic wound healing. The alginate hydrogel is designed using two distinct crosslinking methods to achieve differential degradation, thereby enabling precise spatial and temporal controlled release of PCNs. Initially, interleukin-10 (IL-10) is released to mitigate inflammation, while unsaturated PCNs bind and remove accumulated pro-inflammatory cytokines at the wound site. Subsequently, angiogenic growth factors, including vascular endothelial growth factor and platelet-derived growth factor, are released to promote vascularization and vessel maturation. Our results demonstrate that the bilayer hydrogel exhibits distinct degradation kinetics between the two layers, facilitating the staged release of multiple signaling molecules. In vitro experiments reveal that IL-10 can activate the Jak1/STAT3 pathway, thereby suppressing pro-inflammatory cytokines and chemokines while down-regulating inflammation-related genes. In vivo studies demonstrate that application of the hydrogel in chronic wounds using diabetic murine model promotes healing by positively modulating multiple integral reparative mechanisms. These include reducing inflammation, promoting macrophage polarization towards a pro-regenerative phenotype, enhancing keratinocyte migration, stimulating angiogenesis, and expediting wound closure. In conclusion, our hydrogel system effectively mitigates inflammatory responses and provides essential physiological cues by inducing a synergistic angiogenic effect, thus offering a promising approach for the treatment of chronic wounds.

MicroRNA Signature in an In Vitro Keratinocyte Model of Diabetic Wound Healing.

Treating diabetic wounds effectively remains a significant clinical challenge. Emerging studies suggest that microRNAs (miRNAs) play crucial roles in various physiological and pathological processes and hold promise as therapeutic tools. This study investigates the miRNA expression profile in keratinocytes using a cell model of diabetic wounds. Microarray analysis revealed that 43 miRNAs from wounded keratinocytes incubated under diabetic conditions (high glucose/hypoxia) exhibited a two-fold change in expression compared to those incubated under normal conditions (low glucose/normoxia). Quantitative RT-PCR confirmed significant differences in the expression of eight miRNAs, with miR-3138 and miR-3679-5p being further analyzed for their roles in keratinocyte migration. Transfection with a miR-3138 mimic and a miR-3679-5p inhibitor indicated that upregulation of miR-3138 and downregulation of miR-3679-5p enhance keratinocyte migration in both normal and diabetic wounds. Pathway and gene ontology (GO) analyses identified potential pathways and functional annotations associated with miR-3138 and miR-3679-5p in diabetic wound healing. Potential human gene targets of miR-3138 and miR-3679-5p were predicted using a three-way comparison of the TargetScan, miRDB, and DIANA databases. This study elucidates the miRNA expression signature of human keratinocytes in a diabetes-like environment, providing deeper insights into the pathogenesis of diabetic wounds.

Enhancement of keratinocyte survival and migration elicited by interleukin 24 upregulation in dermal microvascular endothelium upon welding-fume exposure

ABSTRACT Occupational exposure to welding fumes constitutes a serious health concern. Although the effects of fumes on the respiratory tract have been investigated, few apparent reports were published on their effects on the skin. The purpose of this study was to investigate the effects of exposure to welding fumes on skin cells, focusing on interleukin-24 (IL-24), a cytokine involved in the pathophysiology of skin conditions, such as atopic dermatitis and psoriasis. Treatment with welding fumes increased IL-24 expression and production levels in human dermal microvascular endothelial cells (HDMEC) which were higher than that in normal human epidermal keratinocytes. IL-24 levels in Trolox and deferoxamine markedly suppressed welding fume-induced IL-24 expression in HDMEC, indicating that oxidative stress may be involved in this cytokine expression. IL-24 released from HDMEC protected keratinocytes from welding fume-induced damage and enhanced keratinocyte migration. Serum IL-24 was higher in welding workers than in general subjects and was positively correlated with elevated serum levels of 8-hydroxy-2’-deoxyguanosine, an oxidative stress marker. In summary, welding fumes enhanced IL-24 expression in HDMEC, stimulating keratinocyte survival and migration. IL-24 expression in endothelial cells may act as an adaptive response to welding-fume exposure in the skin.

1489 TRPV4 promotes cutaneous wound healing by enhancing keratinocyte migration via MAPK signaling and regulating TGF-β induced differentiation in fibroblasts

1489 TRPV4 promotes cutaneous wound healing by enhancing keratinocyte migration via MAPK signaling and regulating TGF-β induced differentiation in fibroblasts

Bacterial Pyocyanin Inducible Keratin 6A Accelerates Closure of Epithelial Defect under Conditions of Mitochondrial Dysfunction

Repair of epithelial defect is complicated by infection and related metabolites. Pyocyanin (PYO) is one such metabolite that is secreted during Pseudomonas aeruginosa infection. Keratinocyte (KC) migration is required for the closure of skin epithelial defects. This work sought to understand PYO-KC interaction and its significance in tissue repair. Stable Isotope Labeling by Amino acids in Cell culture proteomics identified mitochondrial dysfunction as the top pathway responsive to PYO exposure in human KCs. Consistently, functional studies showed mitochondrial stress, depletion of reducing equivalents, and adenosine triphosphate. Strikingly, despite all stated earlier, PYO markedly accelerated KC migration. Investigation of underlying mechanisms revealed, to our knowledge, a previously unreported function of keratin 6A in KCs. Keratin 6A was PYO inducible and accelerated closure of epithelial defect. Acceleration of closure was associated with poor quality healing, including compromised expression of apical junction proteins. This work recognizes keratin 6A for its role in enhancing KC migration under conditions of threat posed by PYO. Qualitatively deficient junctional proteins under conditions of defensive acceleration of KC migration explain why an infected wound close with deficient skin barrier function as previously reported.

A wound-friendly antibacterial hyaluronic acid dressing with on-demand removability for infected wound healing

BackgroundAntibacterial activity and on-demand removability are key characteristics governing the effectiveness of clinic wound dressing. However, the excellent tissue adhesion of new dressings is often overemphasized without a detailed discussion of dressing replacement. Besides, the inherent antibacterial ability of dressings is beneficial for promoting the healing of infected wound. Therefore, we rationally design an injectable antibacterial wound dressing with on-demand removability to accelerate infected wound healing.MethodWe design this wound dressing with a simple and feasible method based on the electrostatic self-assembly of hyaluronic acid and ε-polylysine. We investigated the efficacy of this dressing in terms of its microtopography, rheology, self-healing performance, adhesive ability, antimicrobial, hemostatic, on-demand removal properties, and wound healing promotion through various tests.ResultsThe prepared dressing possesses injectability, self-healing ability and antibacterial activity, showing NaCl-triggered on-demand dissolution due to the disruption of electrostatic interactions. When used as dressings for healing full-thickness wounds, it could effectively accelerate wound healing by killing bacteria, downregulating inflammation, promoting collagen deposition, enhancing keratinocyte migration and angiogenesis due to its excellent adhesion ability, favorable hemostatic property, and potent antibacterial performance.ConclusionAll results indicate that this is a simple and practical dressing for clinical application. This strategy provides a novel idea for developing on-demand removal dressings with antibacterial and injectable properties.

Antimicrobial Peptide Pt5‐1c Promotes Keratinocyte Migration and Proliferation via EGFR‐mediated Akt/MAPK/STAT3 pathways

AbstractKeratinocytes, as the most dominant cell type in the epidermis, play multiple roles in skin wound healing. Recently, we have shown that a short antimicrobial peptide Pt5‐1c can promote skin wound healing via enhancing fibroblast proliferation and migration in vitro, and accelerating re‐epithelialization of murine dermal wounds in vivo.[1] However, its effects on keratinocytes is unknown. Here we clearly showed that Pt5‐1c markedly enhanced keratinocyte migration and proliferation. Moreover, Pt5‐1c stimulated keratinocyte activation by inducing the phosphorylation of epidermal growth factor receptor (EGFR), Akt, extracellular signal‐regulated kinase (ERK), p38, and signal transducer and activator of transcription 3 (STAT3) in keratinocytes. Importantly, Pt5‐1c also increased collagen production, stimulated cell proliferation, and enhanced the phosphorylation of Akt, p38 and STAT3 in the wound skin tissues. These together indicate that Pt5‐1c can promote keratinocyte migration and proliferation via activation of EGFR‐mediated Akt, MAPK, and STAT3 pathways, thereby contributing to skin wound healing.

Puerarin Improves Dexamethasone-Impaired Wound Healing In Vitro and In Vivo by Enhancing Keratinocyte Proliferation and Migration

The delayed and impaired wound healing caused by dexamethasone (DEX) is commonly reported. Puerarin, the major isoflavone found in Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep promoted the wound healing process in diabetic rats. However, the effects and underlying mechanisms of puerarin on DEX-impaired wound healing have not been investigated. This study examined the potential uses of puerarin in upregulating keratinocyte proliferation and migration in dexamethasone (DEX)-suppressed wound healing model. The effects of puerarin on wound healing in vivo were investigated by taking full-thickness 5 mm punch biopsies from the dorsal skin of BALB/c mice and then treating them topically with 0.1% DEX. For the in vitro study, DEX-treated HaCaT cells were used to examine the effects of puerarin on DEX-induced keratinocyte proliferation and migration and the mechanisms of its action. Puerarin, when applied topically, accelerated the wound closure rate, increased the density of the capillaries, and upregulated the level of collagen fibers and TGF-β in the wound sites compared to the DEX-treated mice. Puerarin promoted the proliferation and migration of keratinocytes by activating the ERK and Akt signaling pathways in DEX-treated HaCaT cells. In conclusion, puerarin could be effective in reversing delayed and disrupted wound healing associated with DEX treatments.

Circ_PRKDC knockdown promotes skin wound healing by enhancing keratinocyte migration via miR-31/FBN1 axis.

Circular RNA protein kinase, DNA-activated, catalytic subunit (circ_PRKDC) has been found to impede wound healing in diabetic foot ulcers via regulating keratinocyte proliferation and migration. However, the mechanisms underlying circ_PRKDC in skin wound healing remain unclear. The expression of circ_PRKDC, microRNA (miR)-31 and fibrillin 1 (FBN1) was detected using quantitative reverse transcription-polymerase chain reaction and Western blot assays. The migration ability and the changes of matrix metallopeptidase 9 (MMP-9) and MMP2 levels were determined using wound healing, transwell and Western blot assays. The interaction between miR-31 and circ_PRKDC or FBN1 was verified by dual-luciferase reporter assay. The expression of circ_PRKDC was gradually down-regulated in wound edge at 1 and 7 days after injury relative to the unwounded skin. In human epidermal keratinocytes (HEKa), knockdown of circ_PRKDC promoted cell migration partly through up-regulating MMP-2 and MMP9, while circ_PRKDC overexpression showed opposite effects. In a mechanical study, we confirmed that miR-31 was a target of circ_PRKDC, and inhibition of miR-31 reversed the promotive effect of circ_PRKDC knockdown on HEKa migration. Besides that, miR-31 was verified to target FBN1, and ectopic overexpression of miR-31 accelerated HEKa migration via FBN1. Importantly, we also demonstrated that FBN1 overexpression attenuated the effects of circ_PRKDC knockdown on HEKa migration. In all, circ_PRKDC knockdown promoted HEKa migration during wound healing through miR-31/FBN1 axis, suggesting the therapeutic potential for circ_PRKDC on skin wound healing.

Enhancing wound healing in recalcitrant leg ulcers with aminolevulinic acid-mediated antimicrobial photodynamic therapy.

Chronic leg ulcers effect millions of people around the world. It is imperative to search for effective treatments for such challenging ulcers. We report the success of aminolevulinic acid-mediated antimicrobial photodynamic therapy (A-PDT) to enhance wound healing of chronic ulcers for 3 patients who were refractory to conventional treatments. These ulcers healed after one to three sessions of A-PDT and there was no recurrence for more than 29 months. Interestingly, no bacteria were isolated from the ulcers after A-PDT treatment. In vitro, A-PDT also inactivated all bacteria isolated from the patients. A-PDT conditioned medium containing IL-6 enhanced keratinocyte migration. The results suggest in addition to bactericidal effects, A-PDT also alters the wound microenvironment. A-PDT may be an effective treatment for patients with recalcitrant infected ulcers.

First Structure-Activity Relationship Study of Potent BLT2 Agonists as Potential Wound-Healing Promoters.

The first potent leukotriene B4 (LTB4) receptor type 2 (BLT2) agonists, endogenous 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT), and synthetic CAY10583 (CAY) have been recently described to accelerate wound healing by enhanced keratinocyte migration and indirect stimulation of fibroblast activity in diabetic rats. CAY represents a very valuable starting point for the development of novel wound-healing promoters. In this work, the first structure-activity relationship study for CAY scaffold-based BLT2 agonists is presented. The newly prepared derivatives showed promising in vitro wound-healing activity.

Electroceutical Management of Bacterial Biofilms and Surgical Infection.

Significance: In the host-microbe microenvironment, bioelectrical factors influence microbes and hosts as well as host-microbe interactions. This article discusses relevant mechanistic underpinnings of this novel paradigm. It also addresses how such knowledge may be leveraged to develop novel electroceutical solutions to manage biofilm infection. Recent Advances: Systematic review and meta-analysis of several hundred wound studies reported a 78.2% prevalence of biofilms in chronic wounds. Biofilm infection is a major cause of delayed wound healing. In the host-microbe microenvironment, bioelectrical factors influence interactions between microbes and hosts. Critical Issues: Rapid biological responses are driven by electrical signals generated by ion currents moving across cell membranes. Bacterial life, growth, and function rely on a bioelectrical milieu, which when perturbed impairs their ability to form a biofilm, a major threat to health care. Electrokinetic stability of several viral particles depend on electrostatic forces. Weak electrical field strength, otherwise safe for humans, can be anti-microbial in this context. In the host, the electric field enhanced keratinocyte migration, bolstered immune defenses, improved mitochondrial function, and demonstrated multiple other effects consistent with supporting wound healing. A deeper mechanistic understanding of bioelectrical principles will inform the design of next-generation electroceuticals. Future Directions: This is an opportune moment in time as there is a surge of interest in electroceuticals in medicine. Projected to reach $35.5 billion by 2025, electroceuticals are becoming a cynosure in the global market. The World Health Organization reports that more than 50% of surgical site infections can be antibiotic resistant. Electroceuticals offer a serious alternative.

LOXL2 from human amniotic mesenchymal stem cells accelerates wound epithelialization by promoting differentiation and migration of keratinocytes.

In this study, we identified wound healing-related proteins secreted by human amniotic epithelial cells (hAECs) and human amniotic mesenchymal stem cells (hAMSCs). We observed increased migration and reduced proliferation and differentiation when keratinocytes were co-cultured in media conditioned by hAECs (hAECs-CM) and hAMSCs (hAMSCs-CM). Label-free mass spectrometry and bioinformatic analyses of the hAECs-CM and hAMSCs-CM proteome revealed several proteins associated with wound healing, angiogenesis, cellular differentiation, immune response and cell motility. The levels of the proteins related to wound healing, including CTHRC1, LOXL2 and LGALS1, were significantly higher in hAMSCs-CM than hAECs-CM. LOXL2 significantly enhanced in vitro keratinocyte migration and differentiation compared to CTHRC1 and LGALS1. Moreover, LOXL2 enhanced keratinocyte migration and differentiation by activating the JNK signaling pathway. We observed significant reduction in the in vitro migration and differentiation of keratinocytes when co-cultured with medium conditioned by LOXL2-silenced hAMSCs and when treated with 10 μM SP600125, a specific JNK inhibitor. Treatment with hAMSCs-CM and LOXL2 significantly accelerated wound healing in the murine skin wound model. These findings show that LOXL2 promotes wound healing by inducing keratinocyte migration and differentiation via a JNK signaling pathway.

633 Human skin long noncoding RNA WAKMAR1 regulates wound healing by enhancing keratinocyte migration

633 Human skin long noncoding RNA WAKMAR1 regulates wound healing by enhancing keratinocyte migration

Topical Alpha-Gal Nanoparticles Enhances Wound Healing in Radiated Tissue

BACKGROUND: Radiation is a common primary, adjuvant, and neoadjuvant therapy in oncologic patients. It is well known that surgery on radiated tissues is associated with significantly higher complication rates due to permanently compromised wound healing. It is thought that one cause of impaired wound healing is the aberrant inflammatory response that occurs in radiated tissues. Previous work has demonstrated that the topical application of naturally occurring antigen α-gal (Galα1-3Galb1-[3]4GlcNAc-R) nanoparticles (AGNs) onto wound surface accelerates macrophage recruitment. As we have already observed accelerated wound healing in both normal and diabetic wounds treated with topical AGN, we hypothesized that application of this natural antigen would similarly enhance healing of the wounds in irradiated tissue. METHODS: To simulate human physiology, α-1,3galactosyltransferase knockout mice (KO), which do not produce the antigen and therefore can be stimulated to produce antibodies against it, were used. KO were exposed to the antigen to produce anti α-gal antibodies at titers comparable to those seen in humans. Ten days before wounding, dorsal skin was isolated using a low-pressure clamp as previously described and was irradiated with one session of 40 Gy. Bilateral 6-mm dorsal splinted full-thickness wounds were created and treated with AGN in a 2% carboxymethyl cellulose carrier, immediately after wounding and again on postoperative day 1. Control knocked out group underwent similar irradiation and wounding protocols but were treated with phosphate buffered saline (PBS) in 2% carboxymethyl cellulose. Wild-type mice, which are indolent to the antigen, went through the same radiation and wounding to eliminate confounding factors other than immunogenic response to AGN. Wounds were harvested from all animals up to 21 days after the wounding for histologic and immunohistochemistry measures. The extent of keratinocyte migration, neovascularization, and macrophage recruitment was assessed. RESULTS: Full closure of all wounds by day 9 in the nonradiated control compared to no completely closed wounds in the radiated group confirmed the known inhibitory effects of irradiation on wound healing. In addition, histologic changes such as increased epidermal thickness in the skin surrounding the wound further confirmed the effects of irradiation on the skin. Histologic analysis demonstrated enhanced keratinocyte migration in the AGN-treated KO wounds, which was significantly improved in comparison to PBS-treated KO wounds noted by day 15 and until the end of the study (P < 0.01). On day 21, ≈63% of all α-gal–treated wounds were completely healed as opposed to only ≈17% in the PBS-treated group. In wild-type mice, treatment with AGN showed no improvement in keratinocyte migration or time to full closure. CONCLUSIONS: Topical application of AGN onto radiated wounds significantly ameliorate the delayed wound healing in radiated tissue resulting in faster wound closure. We believe that this naturally occurring agent has great promise for clinical translation as it has demonstrated efficacy in not only normal wounds but pathologic (diabetic, radiated) ones as well.

Human skin long noncoding RNA WAKMAR1 regulates wound healing by enhancing keratinocyte migration

An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-β signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed "wound and keratinocyte migration-associated lncRNA 1" (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds.

1412 AMP-IBP5, an antimicrobial peptide derived from insulin-like growth factor-binding protein 5, triggers human keratinocyte activation

Besides exhibiting direct microbicidal properties, antimicrobial peptides also display various immunomodulatory functions, including keratinocyte production of cytokines and chemokines, proliferation, migration and wound healing. Recently, a novel antimicrobial peptide named AMP- IBP5 (antimicrobial peptide derived from insulin-like growth factor-binding protein 5) was shown to exhibit antimicrobial activity against numerous pathogens, even at concentrations comparable to those of well-known antimicrobial peptides, such as human β-defensins and LL-37. However, the immunomodulatory role of AMP-IBP5 in cutaneous tissue is still not well understood. In the current study, we investigated whether AMP-IBP5 might trigger human keratinocyte activation and clarified the underlying molecular mechanism. The results revealed that among various cytokines, chemokines and growth factors tested in normal human keratinocytes, AMP-IBP5 selectively increased the production of interleukin (IL-8) and vascular endothelial growth factor (VEGF). Moreover, AMP-IBP5 markedly enhanced keratinocyte migration (assessed by in vitro wound closure assay,) and proliferation (analyzed using BrdU incorporation and XTT assays). AMP-IBP5-induced keratinocyte activation was mediated by Mas-related gene (Mrg) X1-X4 receptors with MAPK and NF-κB pathways working downstream, as evidenced by the inhibitory effects of MrgX1-X4 siRNAs and ERK-, JNK-, p38- and NF-κB-specific inhibitors. Indeed, we confirmed that AMP-IBP5 induced ERK, JNK, p38 and IB phosphorylation. Furthermore, AMP-IBP5-induced VEGF but not IL-8 production correlated with an increase in intracellular cAMP. In conclusion, these observations suggest that in addition to its antimicrobial function, AMP-IBP5 might contribute to wound healing process through activation of human keratinocytes.

665 6-formylindolo[3,2-b]carbazole (FICZ) accelerates skin wound healing via activation of ERK, but not aryl hydrocarbon receptor

Wound healing is an elaborate process composed of overlapping phases, such as proliferation and remodeling, and is delayed in several circumstances, including diabetes. Although several treatment strategies for chronic wounds, such as growth factors, have been applied, further alternatives are required. The skin, especially keratinocytes, is continually exposed to UV rays, which impairs wound healing. The 6-formylindolo[3,2-b]carbazole (FICZ) is a tryptophan photoproduct formed by UV exposure, indicating that FICZ might be one of the effectors of UV radiation. Therefore, the aim of our study is to determine the role of FICZ in wound healing. Here we showed that FICZ enhanced keratinocyte migration through MEK/ERK activation, and promoted wound healing in various mouse models, including db/db mice, which exhibit wound healing impairments because of type 2 diabetes. Moreover, FICZ, the endogenous ligand of aryl hydrocarbon receptor (AhR), accelerated migration even in AhR knockdown condition, and also promoted wound healing in DBA/2 mice, bearing a low-affinity AhR, suggesting that FICZ enhanced keratinocyte migration in an MEK/ERK-dependent, but AhR-independent, manner. The function of FICZ might indicate the possibility of its clinical use for intractable chronic wounds.

EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis.

Epithelial carcinomas are well known to activate a prolonged wound-healing program that promotes malignant transformation. Wound closure requires the activation of keratinocyte migration via a dual-state molecular switch. This switch involves production of either the anti-migratory microRNA miR-198 or the pro-migratory follistatin-like 1 (FSTL1) protein from a single transcript; miR-198 expression in healthy skin is down-regulated in favor of FSTL1 upon wounding, which enhances keratinocyte migration and promotes re-epithelialization. Here, we reveal a defective molecular switch in head and neck squamous cell carcinoma (HNSCC). This defect shuts off miR-198 expression in favor of sustained FSTL1 translation, driving metastasis through dual parallel pathways involving DIAPH1 and FSTL1. DIAPH1, a miR-198 target, enhances directional migration through sequestration of Arpin, a competitive inhibitor of Arp2/3 complex. FSTL1 blocks Wnt7a-mediated repression of extracellular signal-regulated kinase phosphorylation, enabling production of MMP9, which degrades the extracellular matrix and facilitates metastasis. The prognostic significance of the FSTL1-DIAPH1 gene pair makes it an attractive target for therapeutic intervention.