Luminescent Human iPSC-Derived Neurospheroids Enable Modeling of Neurotoxicity After Oxygen-glucose Deprivation

Autor: Elise Van Breedam, Aleksandra Nijak, Tamariche Buyle-Huybrecht, Julia Di Stefano, Marlies Boeren, Jonas Govaerts, Alessandra Quarta, Tine Swartenbroekx, Eva Z. Jacobs, Björn Menten, Rik Gijsbers, Peter Delputte, Maaike Alaerts, Behrouz Hassannia, Bart Loeys, Zwi Berneman, Jean-Pierre Timmermans, Philippe G. Jorens, Tom Vanden Berghe, Erik Fransen, An Wouters, Winnok H. De Vos, Peter Ponsaerts
Rok vydání: 2022
Předmět:
Zdroj: Neurotherapeutics
ISSN: 1878-7479
1933-7213
Popis: Despite the considerable impact of stroke on both the individual and on society, a neuroprotective therapy for stroke patients is missing. This is partially due to the current lack of a physiologically relevant human in vitro stroke model. To address this problem, we have developed a luminescent human iPSC-derived neurospheroid model that enables real-time read-out of neural viability after ischemia-like conditions. We subjected 1- and 4-week-old neurospheroids, generated from iPSC-derived neural stem cells, to 6 h of oxygen–glucose deprivation (OGD) and measured neurospheroid luminescence. For both, we detected a decrease in luminescent signal due to ensuing neurotoxicity, as confirmed by conventional LDH assay and flow cytometric viability analysis. Remarkably, 1-week-old, but not 4-week-old neurospheroids recovered from OGD-induced injury, as evidenced by their reduced but overall increasing luminescence over time. This underscores the need for more mature neurospheroids, more faithfully recapitulating the in vivo situation. Furthermore, treatment of oxygen- and glucose-deprived neurospheroids with the pan-caspase inhibitor Z-VAD-FMK did not increase overall neural survival, despite its successful attenuation of apoptosis, in a human-based 3D environment. Nevertheless, owing to its three-dimensional organization and real-time viability reporting potential, the luminescent neurospheroids may become readily adopted in high-throughput screens aimed at identification of new therapeutic agents to treat acute ischemic stroke patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01212-z.
Databáze: OpenAIRE
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