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

Mol Neurobiol. 2018 Aug;55(8):6965-6983. doi: 10.1007/s12035-018-0913-3. Epub 2018 Jan 25.

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

MeSH terms

  • Actomyosin / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Biomarkers / metabolism
  • Cells, Cultured
  • Culture Media
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Facial Nerve / drug effects
  • Facial Nerve / physiology*
  • Female
  • Gingiva / cytology*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Lamins / pharmacology
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Myosin Type II / metabolism
  • Nerve Regeneration / physiology*
  • Neural Crest / cytology*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / transplantation*
  • Peptides / pharmacology
  • Phosphoproteins / metabolism
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Spheroids, Cellular / cytology
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Transcription Factors
  • Transforming Growth Factor beta / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Culture Media
  • Lamins
  • Peptides
  • Phosphoproteins
  • Transcription Factors
  • Transforming Growth Factor beta
  • YAP1 (Yes-associated) protein, human
  • polyornithine
  • Actomyosin
  • Glycogen Synthase Kinase 3 beta
  • Myosin Type II
  • rhoA GTP-Binding Protein