Enhanced Dopamine Release by Mesenchymal Stem Cells Reprogrammed Neuronally by the Modulators of SMAD Signaling, Chromatin Modifying Enzymes, and Cyclic Adenosine Monophosphate Levels

Recently, using the chemical genetics approach for cell reprogramming, via the combination of small molecule modulators of chromatin modifying enzymes, specific SMAD signaling pathways, and cyclic adenosine monophosphate levels, we have been able to generate neuronallike cells predominantly positive to mature neuronal and dopaminergic markers. This study aimed to characterize further the dopaminergic properties of neurally induced (NI) human bone marrow-derived mesenchymal stem cells (hMSCs) and to determine whether addition of sonic hedgehog (SHH)/fibroblast growth factor 8 (FGF8) to NI medium could promote further dopaminergic maturation. Dopaminergic differentiation was evaluated by immunocytochemistry, reverse transcription-polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Results demonstrated that release of dopamine by NI-hMSCs differentiated with SMAD inhibitor supplementation significantly increased from picogram to nanogram levels, with a tendency of further increase when supplemented by SHH/FGF8. Direct generation of dopaminergic cells from adult hMSCs by using this reprogramming approach may have significant implications for understanding the mechanism underlying cell plasticity and may open new potentialities for cell replacement therapies.