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MicroRNA-132 promotes fibroblast migration via regulating RAS p21 protein activator 1 in skin wound healing.

ABSTRACT: MicroRNA (miR)-132 has been identified as a top up-regulated miRNA during skin wound healing and its inhibition impairs wound repair. In a human in vivo surgical wound model, we showed that miR-132 was induced in epidermal as well as in dermal wound-edge compartments during healing. Moreover, in a panel of cells isolated from human skin wounds, miR-132 was found highly expressed in human dermal fibroblasts (HDFs). In HDFs, miR-132 expression was upregulated by TGF-?1. By overexpression or inhibition of miR-132, we showed that miR-132 promoted HDF migration. Mechanistically, global transcriptome analysis revealed that RAS signaling pathway was regulated by miR-132 in HDFs. We found that RAS p21 protein activator 1 (RASA1), a known target of miR-132, was downregulated in HDFs upon miR-132 overexpression. Silencing of RASA1 phenocopied the pro-migratory effect of miR-132. Collectively, our study reveals an important role for miR-132 in HDFs during wound healing and indicates a therapeutic potential of miR-132 in hard-to-heal skin wounds.

SUBMITTER: Li X

PROVIDER: S-EPMC5552762 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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MicroRNA-132 promotes fibroblast migration via regulating RAS p21 protein activator 1 in skin wound healing.

Li Xi X Li Dongqing D Wikstrom Jakob D JD Pivarcsi Andor A Sonkoly Enikö E Ståhle Mona M Landén Ning Xu NX

Scientific reports 20170810 1

MicroRNA (miR)-132 has been identified as a top up-regulated miRNA during skin wound healing and its inhibition impairs wound repair. In a human in vivo surgical wound model, we showed that miR-132 was induced in epidermal as well as in dermal wound-edge compartments during healing. Moreover, in a panel of cells isolated from human skin wounds, miR-132 was found highly expressed in human dermal fibroblasts (HDFs). In HDFs, miR-132 expression was upregulated by TGF-β1. By overexpression or inhibi ...[more]

PMID: 28798331

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Project description:Wound healing is a well-organized dynamic process involving coordinated consecutive phases: homeostasis, inflammation, proliferation and resolution. Fibroblasts play major roles in skin wound healing such as in wound contraction and release of growth factors which are of importance in angiogenesis and tissue remodeling. Abnormal fibroblast phenotypes have been identified in patients with chronic wounds. In this work, we analyzed scRNA-seq datasets of normal and wounded skin from mice at day 4 post-wound to investigate fibroblast heterogeneity during the proliferative phase of wound healing. Compositional analysis revealed a specific subset of fibroblast (cluster 3) that primarily increased in wounded skin (14%) compared to normal skin (3.9%). This subset was characterized by a gene signature marked by the plasma membrane proteins Sfrp2 + Sfrp4 + Sfrp1 + and the transcription factors Ebf1 + Prrx1 + Maged1 + . Differential gene expression and enrichment analysis identified epithelial to mesenchymal transition (EMT) and angiogenesis to be upregulated in the emerging subset of fibroblasts of the wounded skin. Using two other datasets for murine wounded skin confirmed the increase in cluster 3-like fibroblasts at days 2, 7 and 14 post-wounding with a peak at day 7. By performing a similarity check between the differential gene expression profile between wounded and normal skin for this emerging fibroblast subset with drug signature from the ConnectivityMap database, we identified drugs capable of mimicking the observed gene expression change in fibroblasts during wound healing. TTNPB, verteprofin and nicotinic acid were identified as candidate drugs capable of inducing fibroblast gene expression profile necessary for wound healing. On the other hand, methocarbamol, ifosfamide and penbutolol were recognized to antagonize the identified fibroblast differential expression profile during wound healing which might cause delay in wound healing. Taken together, analysis of murine transcriptomic skin wound healing datasets suggested a subset of fibroblasts capable of inducing EMT and further inferred drugs that might be tested as potential candidates to induce wound closure.

Project description:Skin injuries are frequently encountered in daily life, but deep wounds often poorly self-heal and do not recover completely. In this study, we propose a novel skin patch that combines antibiotic, cell-derived extracellular matrix (ECM) and biocompatible polyvinyl alcohol (PVA) hydrogel. Methods: Decellularized human lung fibroblast-derived matrix (hFDM) was prepared on tissue culture plate (TCP) and PVA solution was then poured onto it. After a freeze-thaw process, PVA was peeled off from TCP along with hFDM tightly anchored to PVA. Subsequently, ciprofloxacin (Cipro)-incorporated PVA/hFDM (PVA/Cipro/hFDM) was fabricated via diffusion-based drug loading. Results: In vitro analyses of PVA/Cipro/hFDM show little cytotoxicity of ciprofloxacin, stability of hFDM, rich fibronectin in hFDM, and good cell attachment, respectively. In addition, hFDM proved to be beneficial in promoting cell migration of dermal fibroblasts and human umbilical vein endothelial cells (HUVECs) using transwell inserts. The antibacterial drug Cipro was very effective in suppressing colony growth of gram-negative and -positive bacteria as identified via an inhibition zone assay. For animal study, infected wound models in BALB/c mice were prepared and four test groups (control, PVA, PVA/Cipro, PVA/Cipro/hFDM) were administered separately and their effect on wound healing was examined for up to 21 days. The results support that Cipro successfully reduced bacterial infection and thus encouraged faster wound closure. Further analysis using histology and immunofluorescence revealed that the most advanced skin regeneration was achieved with PVA/Cipro/hFDM, as assessed via re-epithelialization, collagen texture and distribution in the epidermis, and skin adnexa (i.e., glands and hair follicles) regeneration in the dermis. Conclusion: This work demonstrates that our skin patch successfully consolidates the regenerative potential of ECM and the antibacterial activity of Cipro for advanced wound healing.

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MicroRNA-132 promotes fibroblast migration via regulating RAS p21 protein activator 1 in skin wound healing.

Publications

MicroRNA-132 promotes fibroblast migration via regulating RAS p21 protein activator 1 in skin wound healing.

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