Development of a human iPSC-derived corticospinal tract-on-a-chip

Degeneration of the corticospinal tract is a feature in several neurodegenerative disorders and leads to disability. However, modeling corticospinal neuron (CSN) pathology and corticospinal connectivity is challenging, as there are interspecies differences in these networks. We developed a human induced pluripotent stem cell (hiPSC)-based microfluidic platform for modeling human CSN and spinal motor neuron (SpMN) connectivity. The incorporation of regionally specific astrocyte subtypes (cortical and spinal) in addition to CSNs and SpMNs allows for the modeling of neural cell interactions. Multielectrode array electrophysiology reveals the temporal maturation of the network. Retrograde labeling demonstrates synaptic connectivity between CSNs and SpMN. Optogenetic strategies to selectively activate excitatory cortical neurons (CNs) attenuated by glutamate receptor antagonism confirm the functional relevance of the model. Incorporating morphological, electrophysiological, and physiological measures of corticospinal connectivity, this platform is a versatile model for neurodegenerative disease research and the future development of targeted CSN therapies.