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Abstract The transplantation of stem cells has considerable potential in delaying the progression of Parkinson's disease (PD). Both the source of the stem cells and the method of differentiation induction are critical factors in this process. In the present work, for the first time, we developed a differentiation strategy that allows for the generation of functional dopaminergic (DA) neurons from skin-derived precursor cells (SKPs). Concurrently, intercellular tunneling nanotubes (TNTs) and substance transfer were observed in a direct coculture system of SKP-induced differentiated dopaminergic neurons (SKP-DA neurons) and primary DA neurons. Furthermore, we assessed the survival, differentiation, migration of SKP-DA neurons and enhancement of striatal functional deficits in the PD model after SKP-DA neurons transplantation. The intranasal administration of SKP-DA neurons resulted in effective survival and differentiation into DA neurons without the formation of tumors, thereby leading to improvements in the functional deficits of the PD model. This study provides evidence that SKPs undergoing induced differentiation can develop the morphological characteristics and functional properties of DA neurons, thereby improving the functional deficits associated with PD. These findings suggest the potential of noninvasive treatment as a novel regenerative therapeutic approach for PD.
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