Spatiotemporal microRNA profile in peripheral nerve regeneration: miR-138 targets vimentin and inhibits Schwann cell migration and proliferation

Abstract

While the peripheral nervous system has regenerative ability, restoration of sufficient function remains a challenge. Vimentin has been shown to be localized in axonal growth fronts and associated with nerve regeneration, including myelination, neuroplasticity, kinase signaling in nerve axoplasm, and cell migration; however, the mechanisms regulating its expression within Schwann cell (SC) remain unexplored. The aim of this study was to profile the spatial and temporal expression profile of microRNA (miRNA) in a regenerating rat sciatic nerve after transection, and explore the potential role of miR-138-5p targeting vimentin in SC proliferation and migration. A rat sciatic nerve transection model, utilizing a polyethylene nerve guide, was used to investigate miRNA expression at 7, 14, 30, 60, and 90 days during nerve regeneration. Relative levels of miRNA expression were determined using microarray analysis and subsequently validated with quantitative real-time polymerase chain reaction. In vitro assays were conducted with cultured Schwann cells transfected with miRNA mimics and assessed for migratory and proliferative potential. The top seven dysregulated miRNAs reported in this study have been implicated in cell migration elsewhere, and GO and KEGG analyses predicted activities essential to wound healing. Transfection of one of these, miRNA-138-5p, into SCs reduced cell migration and proliferation. miR-138-5p has been shown to directly target vimentin in cancer cells, and the luciferase assay performed here in rat Schwann cells confirmed it. These results detail a role of miR-138-5p in rat peripheral nerve regeneration and expand on reports of it as an important regulator in the peripheral nervous system.

Associations between miR-146a rs2910164 polymorphisms and risk of ischemic cardio-cerebrovascular diseases

“…[9] Epidemiological studies demonstrated that miRNA-associated genetic sequence polymorphism played an important role in the development and progression of diseases including neurological disorders, cardiovascular diseases, autoimmune diseases, and cancers. [10] Accumulating evidences have demonstrated that miR-146a participates in inflammatory processes to interfere with the pathology of cardiovascular diseases. In addition, miR-146a also exerts a neuroprotective effect through astrocytes to downregulated miR-146a in patients with ischemic stroke (IS) in the acute phase.…”

Epidermal stem cells in wound healing and their clinical applications

“…miRNAs are small, noncoding RNAs that regulate gene expression posttranscriptionally, which play key roles in epidermal development and skin SC maintenance [94, 95]. miR-203 plays a significant role in skin morphogenesis and EPSC differentiation and inhibits “stemness” by inhibiting the expression of p63 [96].…”

Epigenetic regulation of myelination in health and disease

“…Interestingly, although miR-138 is substantially reduced in Dicer1 and Dgcr8 knockout mice, miR-138 mutant mice did not show significant changes in Schwann cell proliferation and myelination (Lin, Oksuz, Svaren, & Awatramani, 2018). However, in rat sciatic nerve after transection, Travis found miR-138 could inhibit SCs migration and proliferation (Sullivan et al, 2018), indicating its function in injury instead of in development. Besides, the involvement of miR-210 and miR-132 in rat sciatic nerve injury further suggested their applications in promoting PNS remyelination Zhang, Gong, Qiu, Zhang, & Gong, 2017).…”