Induction of neuronal-like phenotype in human mesenchymal stem cells by overexpression of Neurogenin1 and treatment with neurotrophins.

AIM OF THE STUDY:The induced expression of the transcription factors neurogenin1 (Neurog1) or neuronal differentiation 1 (NeuroD1) has previously been shown to initiate neuronal differentiation in embryonic stem cells (ESC). Human bone marrow-derived mesenchymal stem cells (hBMSCs) are ethically non-controversial stem cells. However, they are not pluripotent. In cochlear implantation, regeneration or replacement of lost spiral ganglion neurons may be a measure for the improvement of implant function. Thus, the aim of the study was to investigate whether the expression of Neurog1 or NeuroD1 is sufficient for induction of neuronal differentiation in hBMSCs. MATERIALS AND METHODS:Human BMSCs were transduced with lentivirus expressing NeuroD1 or Neuorg1. Transduced cells were then treated with small molecules that enhanced neuronal differentiation. Markers of neuronal differentiation were evaluated. RESULTS:Using quantitative reverse transcription PCR, the up-regulation of transcription factors expressed by developing primary auditory neurons, such as BRN3a (POU4F1) and GATA3, was quantified after induction of Neurog-1 expression. In addition, the expression of the receptor NTRK2 was induced by treatment with its specific ligand BDNF. The induction of expression of the vesicular glutamate transporter 1 was identified on gene and protein level. NeuroD1 seemed not sufficient to induce and maintain neuronal differentiation. CONCLUSIONS:Induction of neuronal differentiation by overexpression of Neurog1 initiated important steps for the development of glutamatergic neurons such as the spiral ganglion neurons. However, it seems not sufficient to maintain the glutamatergic spiral ganglion neuron-like phenotype.

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