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Neural Crest Stem-Like Cells Non-genetically Induced from Human Gingiva-Derived Mesenchymal Stem Cells Promote Facial Nerve Regeneration in Rats

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Abstract

Non-genetic induction of somatic cells into neural crest stem-like cells (NCSCs) is promising for potential cell-based therapies for post-traumatic peripheral nerve regeneration. Here, we report that human gingiva-derived mesenchymal stem cells (GMSCs) could be reproducibly and readily induced into NCSCs via non-genetic approaches. Compared to parental GMSCs, induced NCSC population had increased expression in NCSC-related genes and displayed robust differentiation into neuronal and Schwann-like cells. Knockdown of the expression of Yes-associated protein 1 (YAP1), a critical mechanosensor and mechanotransducer, attenuated the expression of NCSC-related genes; specific blocking of RhoA/ROCK activity and non-muscle myosin II (NM II)-dependent contraction suppressed YAP1 and NCSC-related genes and concurrently abolished neural spheroid formation in NCSCs. Using a rat model of facial nerve defect, implantation of NCSC-laden nerve conduits promoted functional regeneration of the injured nerve. These promising findings demonstrate that induced NCSCs derived from GMSCs represent an easily accessible and promising source of neural stem-like cells for peripheral nerve regeneration.

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Funding

This work was supported by the National Institute of Health Research Grant, R01DE 019932 (to A. L.), the Osteo Science Foundation (OSF) (to Q. Z. Z., and A. L.), Oral and Maxillofacial Surgery Foundation (OMSF) Research Support Grant (to Q. Z. Z. and A. L.), the Schoenleber Funding Support (A. L.), and the US Department of Defense, W81XWH-16-1-0796 & W81XWH-15-1-0466 (to D. K. C.).

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, 240 South 40th Street, Philadelphia, PA, 19104, USA

    Qunzhou Zhang, Shihong Shi, Qilin Xu & Anh D. Le

  2. Division of Plastic and Reconstructive Surgery, University of Pennsylvania Perelman School of Medicine, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Phuong D. Nguyen

  3. Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, 3320 Smith Walk, Philadelphia, PA, 19104, USA

    Justin C. Burrell & Kacy D. Cullen

  4. Department of Oral and Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Anh D. Le

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  1. Qunzhou Zhang
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Qunzhou Zhang: Conception and Design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing. Phuong D. Nguyen: Collection and/or assembly of data. Shihong Shi: Collection and/or assembly of data. Justin C. Burrell: Collection and/or assembly of data. Kacy D. Cullen: Conception and Design, Manuscript writing. Anh D. Le: Conception and Design, Manuscript writing, Final approval of manuscript.

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Zhang, Q., Nguyen, P.D., Shi, S. et al. Neural Crest Stem-Like Cells Non-genetically Induced from Human Gingiva-Derived Mesenchymal Stem Cells Promote Facial Nerve Regeneration in Rats. Mol Neurobiol 55, 6965–6983 (2018). https://doi.org/10.1007/s12035-018-0913-3

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