Human iPSC-Derived Tissue-Engineered Nigrostriatal Pathway for Chronic Restoration of Dopaminergic Axon Tracts in a Rat Parkinson's Model.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine-producing neurons in the substantia nigra, causing motor symptoms. Current surgical interventions fail to restore the native nigrostriatal pathway essential for dopamine regulation. We have developed tissue-engineered nigrostriatal pathways (TE-NSPs) using hyaluronic acid hydrogel microcolumns with a collagen/laminin core encasing aggregated dopaminergic neurons and long-projecting axon tracts. TE-NSPs fabricated using human iPSC-derived dopaminergic neurons extended bundled axon tracts at a rate of 1 mm/day-twice that of neuronal aggregates on planar surfaces. Fully grown engineered microtissue exhibited nigrostriatal-like cytoarchitecture, appropriate dopaminergic phenotypes, evoked dopamine release, and innervation of striatal neurons in vitro. TE-NSPs were then evaluated in a rat 6-OHDA PD model via histology and voltammetry at 3- and 6 months post-implantation. TE-NSPs showed dopaminergic neuronal survival in the substantia nigra, preserved axon tracts within the microcolumn, and outgrowth into host striatum. Voltammetry on ex vivo brain slices containing the implanted microtissue revealed evoked dopamine release at both 3- and 6-months post-implant. This study shows engineered microtissue fabricated using human cells with an anatomically-inspired architecture and subsequently used for chronic replacement of a long-distance brain pathway in a preclinical model, potentially offering a promising future treatment for pathway reconstruction in PD.