Gingiva-Derived Mesenchymal Stem Cell-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration

• Published in: Tissue engineering. Part A 2019-06, Vol.25 (11-12), p.887-900
• Main Authors: Mao, Qin, Nguyen, Phuong D., Shanti, Rabie M., Shi, Shihong, Shakoori, Pasha, Zhang, Qunzhou, Le, Anh D.
• Format: Article
• Language: English
• Subjects: Animals; c-Jun protein; Cell migration; Cell Movement; Cell proliferation; Extracellular vesicles; Extracellular Vesicles - metabolism; Extracellular Vesicles - pathology; Extracellular Vesicles - transplantation; Female; Genotype & phenotype; Gingiva; Gingiva - metabolism; Gingiva - pathology; Glial fibrillary acidic protein; Inflammatory diseases; Injuries; JNK protein; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mesenchyme; Mice; Mimicry; Nerve Regeneration; Notch1 protein; Original Articles; Peripheral Nerve Injuries - metabolism; Peripheral Nerve Injuries - pathology; Peripheral Nerve Injuries - therapy; Peripheral nerves; Phenotypes; Rats; Rats, Sprague-Dawley; Recovery of function; Regeneration; Schwann cells; Schwann Cells - metabolism; Schwann Cells - pathology; Sciatic Nerve - injuries; Sciatic Nerve - physiology; Stem cell transplantation; Stem cells; Tissue engineering; Transcription factors
• ISSN: 1937-3341; 1937-335X
• DOI: 10.1089/ten.tea.2018.0176

A fully functional recovery of peripheral nerve injury remains a major challenge and an unmet clinical need. Recent evidence has reported promising therapeutic effects of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in experimental models of tissue injuries and inflammatory diseases, but less is known about their effects on peripheral nerve regeneration. In this study, we investigated the effects of gingiva-derived mesenchymal stem cell (GMSC)-derived EVs on peripheral nerve regeneration of crush-injured mice sciatic nerves. In vivo studies mimicking clinical nerve repair showed that locally wrapping Gelfoam embedded with GMSC-derived EVs at the crush injury site promoted functional recovery and axonal regeneration, which were comparable with effects conferred by direct transplantation of GMSCs. Mechanistically, we showed that GMSC-derived EVs promoted proliferation and migration of Schwann cells, upregulated the protein expressions of c-JUN, Notch1, GFAP (glial fibrillary acidic protein), and SRY (sex determining region Y)-box 2 (SOX2), characteristic genes of dedifferentiation or repair phenotype of Schwann cells, through which pharmacologically blocking c-JUN/JNK (c-JUN N-terminal kinase) activity significantly abrogated GMSC-derived EV-induced upregulation of these Schwann cell dedifferentiation/repair phenotype-related genes. These findings suggest that GMSC-derived EVs promote peripheral nerve regeneration possibly by activating c-JUN-governed repair phenotype of Schwann cells.