A role for the mitogen-activated protein kinase kinase kinase 1 in epithelial wound healing
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ABSTRACT:
PROVIDER: PRJNA833116 | ENA |
REPOSITORIES: ENA
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Project description:The mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1), also known as MAP3K1, mediates activin B (ActB) signals required for eyelid epithelium morphogenesis during mouse fetal development. The present study investigates the role of MEKK1 in epithelial wound healing, another activin-regulated biological process. In a skin wound model, injury markedly stimulates MEKK1 expression and activity, which are in turn required for the expression of genes involved in extracellular matrix (ECM) homeostasis. MEKK1 ablation or down-regulation by interfering RNA significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor (PAI)-1, and restoration of cell-cell junctions of the wounded epidermis. Conversely, expression of wild-type MEKK1 accelerates reepithelialization of full-thickness skin and corneal debridement wounds by mechanisms involving epithelial cell migration, a cell function that is partially abolished by neutralizing antibodies for PAI-1 and metalloproteinase III. Our data suggest that MEKK1 transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization.
2022-07-13 | GSE201823 | GEO
Project description:Wound healing is a multi-step process to rapidly restore barrier function. This process is often impaired in diabetic patients resulting in chronic wounds and amputation. We previously found that paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway via topical administration of the BRAF inhibitor vemurafenib accelerates wound healing by activating keratinocyte proliferation and reepithelialization pathways in healthy mice. Herein, we investigated whether this wound healing acceleration also occurs in impaired diabetic wounds and found that topical vemurafenib not only improves wound healing in a murine diabetic wound model, but unexpectedly promotes hair follicle regeneration. Neogenic hair follicles expressing Sox-9, CD34 and K15 were found in wounds of diabetic and non-diabetic mice, and their formation can be prevented by blocking downstream MEK signaling. Thus, topically applied BRAF inhibitors may accelerate wound healing, and promote the restoration of improved skin architecture in both normal and impaired wounds.
2021-05-22 | GSE148037 | GEO
Project description: Not available
| S-EPMC1525243 | biostudies-literature
Project description:Urinary bladder wound healing is today pooorly chracterized. MicroRNAs are small non-coding RNA molecules with regulatory functions. In this study we aimed at identifying microRNAs expressed during bladder wound healing. We performed Affymetrix microRNA profiling of the rodent urinary bladder during healing of a surgically created wound.
2021-12-01 | GSE176515 | GEO
Project description:S.ciliatum wound healing - transcriptome sequencing
| PRJEB49227 | ENA
Project description:BRAF inhibitors are highly effective therapies for patients with BRAF V600 mutated metastatic melanoma. Patients who receive BRAF inhibitors develop a variety of hyper-proliferative skin conditions, whose pathogenic basis is the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyper-proliferative skin changes improve when a MEK inhibitor is co-administered, as a MEK inhibitor blocks paradoxical MAPK activation. We tested whether we could take advantage of the mechanistic understanding of the skin hyper-proliferative side effects of BRAF inhibitors to accelerate skin wound healing by inducing paradoxical MAPK activation. Here we show that the BRAF inhibitor vemurafenib accelerates human keratinocyte proliferation and migration by increasing ERK phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing models in mice accelerated cutaneous wound healing and improved the tensile strength of healing wounds through paradoxical MAPK activation; addition of a MEK inhibitor reversed the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor did not increase the incidence of cutaneous squamous cell carcinomas in mice even after the application of a carcinogen. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. Full depth incisional wound mice tissues with/without Vemurafenib treatment were sent for RNAseq analysis on day 2, 6 and 14
2016-07-29 | E-GEOD-74558 | biostudies-arrayexpress
Project description:Impaired re-epithelialization is a hallmark of non-healing, chronic skin wounds. These represent major causes of patient morbidity, particularly amongst ever-increasing ageing and diabetic populations, posing significant challenges to healthcare providers worldwide. Despite many treatment options being available, these often offer limited benefits to healing outcomes. We address the need for more efficacious treatments through evaluation of novel epoxy-tigliane compounds as chronic wound pharmaceuticals, based on their effectiveness in promoting keratinocyte healing responses and re-epithelialization in vivo. Here, we identify that prototype epoxy-tigliane (EBC-46) and analogue (EBC-211), accelerate G1/S and S/G2 cell cycle transitions and proliferation in a normal human keratinocyte cell line of skin origin (HaCaTs). EBC-46 and EBC-211 further induce HaCaT migration/wound repopulation, even with mitomycin C treatment, suggesting epoxy-tiglianes can promote migration/repopulation independently of proliferation. Epoxy-tiglianes modulate keratin, DNA synthesis/replication, cell cycle/proliferation, motility/migration, differentiation, proteinase; and cytokine/chemokine gene expression, to facilitate enhanced responses. Although epoxy-tiglianes down-regulate cytokine/chemokine agonists of keratinocyte proliferation/migration, we demonstrate that enhanced HaCaT responses are mediated through protein kinase C (PKC) phosphorylation and abrogated by inhibition of PKC activation with bisindolylmaleimide-1 (BIM-1). By identifying how epoxy-tiglianes stimulate keratinocyte healing responses, we highlight their potential as novel therapeutics for impaired re-epithelialization associated with non-healing, chronic wounds.
2019-08-01 | GSE122297 | GEO
Project description:Diabetic foot ulcers (DFU) are one of the major complications in type II diabetes patients and can result in amputation and morbidity. Although multiple approaches are used clinically to help wound closure, many patients still lack adequate treatment. Here we show that IL-20 subfamily cytokines are upregulated during normal wound healing. While there is a redundant role for each individual cytokine in this subfamily in wound healing, mice deficient in IL-22R, the common receptor chain for IL-20, IL-22, and IL-24, display a significant delay in wound healing. Furthermore, IL-20, IL-22 and IL-24 are all able to promote wound healing in type II diabetic db/db mice. When compared to other growth factors such as VEGF and PDGF that accelerate wound healing in this model, IL-22 uniquely induced genes involved in reepithelialization, tissue remodeling and innate host defense mechanisms from wounded skin. Interestingly, IL-22 treatment showed superior efficacy compared to PDGF or VEGF in an infectious diabetic wound model. Taken together, our data suggest that IL-20 subfamily cytokines, particularly IL-20, IL-22, and IL-24, might provide therapeutic benefit for patients with DFU.
2017-03-08 | GSE80419 | GEO
Project description:The cornea, transparent and outermost structure of camera-type eyes, is prone to environmental challenges, but has remarkable wound healing capabilities which enables to preserve vision. The manner in which cell plasticity impacts wound healing remains to be determined. In this study, we report rapid wound closure after zebrafish corneal epithelium abrasion. Furthermore, by investigating the cellular and molecular events taking place during corneal epithelial closure, we show the induction of a bilateral response to a unilateral wound. Our transcriptomic results, together with our TGF-beta receptor inhibition experiments, demonstrate conclusively the crucial role of TGF-beta signaling in corneal wound healing. Finally, our results on Pax6 expression and bilateral wound healing, demonstrate the decisive impact of epithelial cell plasticity on the pace of healing. Altogether, our study describes terminally differentiated cell competencies in the healing of an injured cornea. These findings will enhance the translation of research on cell plasticity to organ regeneration.
2022-01-20 | GSE193784 | GEO