Nanogrooved substrate promotes direct lineage reprogramming of fibroblasts to functional induced dopaminergic neurons

Abstract

The generation of dopaminergic (DA) neurons via direct lineage reprogramming can potentially provide a novel therapeutic platform for the study and treatment of Parkinson's disease. Here, we showed that nanoscale biophysical stimulation can promote the direct lineage reprogramming of somatic fibroblasts to induced DA (iDA) neurons. Fibroblasts that were cultured on flat, microgrooved, and nanogrooved substrates responded differently to the patterned substrates in terms of cell alignment. Subsequently, the DA marker expressions, acquisition of mature DA neuronal phenotypes, and the conversion efficiency were enhanced mostly on the nanogrooved substrate. These results may be attributed to specific histone modifications and transcriptional changes associated with mesenchymal-to-epithelial transition. Taken together, these results suggest that the nanopatterned substrate can serve as an efficient stimulant for direct lineage reprogramming to iDA neurons, and its effectiveness confirms that substrate nanotopography plays a critical role in the cell fate changes during direct lineage reprogramming.

Keywords: Direct reprogramming; Induced dopaminergic neurons; Mesenchymal-to-epithelial transition; Nanotopography.