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Molecular Neurobiology

, Volume 55, Issue 8, pp 6965–6983 | Cite as

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

  • Qunzhou Zhang
  • Phuong D. Nguyen
  • Shihong Shi
  • Justin C. Burrell
  • Qilin Xu
  • Kacy D. Cullen
  • Anh D. Le
Article

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.

Keywords

Neural crest stem cells Gingiva-derived mesenchymal stem cells YAP1 RhoA/ROCK Facial nerve regeneration 

Notes

Author Contributions

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.

Funding Information

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.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

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Authors and Affiliations

  1. 1.Department of Oral and Maxillofacial Surgery and PharmacologyUniversity of Pennsylvania School of Dental MedicinePhiladelphiaUSA
  2. 2.Division of Plastic and Reconstructive SurgeryUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  3. 3.Department of NeurosurgeryUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  4. 4.Department of Oral and Maxillofacial SurgeryPenn Medicine Hospital of the University of Pennsylvania, Perelman Center for Advanced MedicinePhiladelphiaUSA

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