title: Neural Progenitor-Like Cells Induced from Human Gingiva-Derived Mesenchymal Stem Cells Regulate Myelination of Schwann Cells in Rat Sciatic Nerve Regeneration.
abstract: Regeneration of peripheral nerve injury remains a major clinical challenge. Recently, mesenchymal stem cells (MSCs) have been considered as potential candidates for peripheral nerve regeneration; however, the underlying mechanisms remain elusive. Here, we show that human gingiva-derived MSCs (GMSCs) could be directly induced into multipotent NPCs (iNPCs) under minimally manipulated conditions without the introduction of exogenous genes. Using a crush-injury model of rat sciatic nerve, we demonstrate that GMSCs transplanted to the injury site could differentiate into neuronal cells, whereas iNPCs could differentiate into both neuronal and Schwann cells. After crush injury, iNPCs, compared with GMSCs, displayed superior therapeutic effects on axonal regeneration at both the injury site and the distal segment of the injured sciatic nerve. Mechanistically, transplantation of GMSCs, especially iNPCs, significantly attenuated injury-triggered increase in the expression of c-Jun, a transcription factor that functions as a major negative regulator of myelination and plays a central role in dedifferentiation/reprogramming of Schwann cells into a progenitor-like state. Meanwhile, our results also demonstrate that transplantation of GMSCs and iNPCs consistently increased the expression of Krox-20/EGR2, a transcription factor that governs the expression of myelin proteins and facilitates myelination. Altogether, our findings suggest that transplantation of GMSCs and iNPCs promotes peripheral nerve repair/regeneration, possibly by promoting remyelination of Schwann cells mediated via the regulation of the antagonistic myelination regulators, c-Jun and Krox-20/EGR2. Stem Cells Translational Medicine 2017;6:458-470.
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Qunzhou
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Plastic and Reconstructive Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Wonse
authors.initials: W
authors.lastname: Park
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Sumin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Furuhashi
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.|Department of Oral and Maxillofacial Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002469:Cell Separation; D002478:Cells, Cultured; D000071576:Crush Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D004195:Disease Models, Animal; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005260:Female; D005881:Gingiva / Q000166:cytology*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism* / Q000637:transplantation*; D010641:Phenotype; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000074586:Remyelination; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D015398:Signal Transduction
chemical_list: C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; D016755:Proto-Oncogene Proteins c-jun
keywords: Gingiva-derived mesenchymal stem cell; Induced neural progenitor cells; Myelination; Peripheral nerve regeneration; Schwann cells