Dopaminergic-like neurons derived from oral mucosa stem cells by developmental cues improve symptoms in the hemi-parkinsonian rat model

PLoS One. 2014 Jun 19;9(6):e100445. doi: 10.1371/journal.pone.0100445. eCollection 2014.

Abstract

Achieving safe and readily accessible sources for cell replacement therapy in Parkinson's disease (PD) is still a challenging unresolved issue. Recently, a primitive neural crest stem cell population (hOMSC) was isolated from the adult human oral mucosa and characterized in vitro and in vivo. In this study we assessed hOMSC ability to differentiate into dopamine-secreting cells with a neuronal-dopaminergic phenotype in vitro in response to dopaminergic developmental cues and tested their therapeutic potential in the hemi-Parkinsonian rat model. We found that hOMSC express constitutively a repertoire of neuronal and dopaminergic markers and pivotal transcription factors. Soluble developmental factors induced a reproducible neuronal-like morphology in the majority of hOMSC, downregulated stem cells markers, upregulated the expression of the neuronal and dopaminergic markers that resulted in dopamine release capabilities. Transplantation of these dopaminergic-induced hOMSC into the striatum of hemi-Parkinsonian rats improved their behavioral deficits as determined by amphetamine-induced rotational behavior, motor asymmetry and motor coordination tests. Human TH expressing cells and increased levels of dopamine in the transplanted hemispheres were observed 10 weeks after transplantation. These results demonstrate for the first time that soluble factors involved in the development of DA neurons, induced a DA phenotype in hOMSC in vitro that significantly improved the motor function of hemiparkinsonian rats. Based on their neural-related origin, their niche accessibility by minimal-invasive procedures and their propensity for DA differentiation, hOMSC emerge as an attractive tool for autologous cell replacement therapy in PD.

MeSH terms

  • Adult
  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Cues
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopaminergic Neurons / cytology*
  • Humans
  • Male
  • Mice
  • Mouth Mucosa / cytology*
  • Neostriatum / metabolism
  • Neostriatum / pathology
  • Parkinson Disease / pathology*
  • Parkinson Disease / therapy*
  • Phenotype
  • Rats, Sprague-Dawley
  • Stem Cell Transplantation*
  • Stem Cells / cytology*
  • Transcription Factors / metabolism
  • Tyrosine 3-Monooxygenase / metabolism
  • Young Adult

Substances

  • Biomarkers
  • Transcription Factors
  • Tyrosine 3-Monooxygenase
  • Dopamine

Grants and funding

This work was supported, in part, by the Binational United States – Israel Science Foundation [Grants number 9007002 and 2011017] to Sandu Pitaru [SP]; the Israel Science Foundation of the Israeli Academy of Science [Grants number 646/09 and 384/13] to S.P.; SAIA and MOIA fellowship to J.G. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.