Advances in mechanistic knowledge of human neurological disorders have been hindered by the lack of adequate human <i>in vitro</i> models. 3D cellular models displaying higher biological relevance are gaining momentum, however, their lack of robustness and scarcity of analytical tools adapted to 3D hampers their widespread implementation. Herein we show that human midbrain-derived neural progenitor cells (hmNPC), cultured as 3D neurospheres in stirred culture systems, reproducibly differentiate into complex tissue-like structures containing functional dopaminergic neurons, as well as astrocytes and oligodendrocytes. Moreover, an extensive toolbox of analytical methodologies has been adapted to 3D neural cell models, allowing molecular and phenotypic profiling and interrogation. The generated neurons underwent synaptogenesis and elicit spontaneous Ca<sup>2+</sup> transients. Synaptic vesicle trafficking and release of dopamine in response to depolarizing stimuli was also observed. Under whole-cell current-and-voltage-clamp, recordings showed polarized neurons (Vm ≈-70 mV) and voltage-dependent potassium currents, which included A-type-like currents. Glutamate-induced currents sensitive to AMPA and NMDA antagonists revealed the existence of functional glutamate receptors. Molecular and phenotypic profiling showed recapitulation of midbrain patterning events, and remodeling towards increased similarity to human brain features such as ECM composition and metabolic signature. We have developed a robust and reproducible human 3D neural cell model, which may be extended to patient-derived iPSC, broadening the applicability of this model.
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 November 2015.
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