Establishment of human pluripotent stem cell-derived cortical neurosphere model to study pathomechanisms and chemical toxicity in Kleefstra syndrome.

Autor: Balogh A; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Bódi-Jakus M; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Karl VR; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Bellák T; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary.; Department of Anatomy, Histology and Embryology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, 6724, Hungary., Széky B; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Farkas J; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Lamberto F; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary.; Department of Physiology and Animal Health, Institute of Physiology and Animal Nutrition, Hungarian University of Agriculture and Life Sciences, Gödöllő, H-2100, Hungary., Novak D; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Fehér A; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Zana M; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary., Dinnyés A; BioTalentum Ltd, Aulich Lajos Street 26, Gödöllő, 2100, Hungary. andras.dinnyes@biotalentum.hu.; Department of Physiology and Animal Health, Institute of Physiology and Animal Nutrition, Hungarian University of Agriculture and Life Sciences, Gödöllő, H-2100, Hungary. andras.dinnyes@biotalentum.hu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Sep 29; Vol. 14 (1), pp. 22572. Date of Electronic Publication: 2024 Sep 29.
DOI: 10.1038/s41598-024-72791-4
Abstrakt: In the present study, we aimed to establish and characterize a mature cortical spheroid model system for Kleefstra syndrome (KS) using patient-derived iPSC. We identified key differences in the growth behavior of KS spheroids determined by reduced proliferation marked by low Ki67 and high E-cadherin expression. Conversely, in the spheroid-based neurite outgrowth assay KS outperformed the control neurite outgrowth due to higher BDNF expression. KS spheroids were highly enriched in VGLUT1/2-expressing glutamatergic and ChAT-expressing cholinergic neurons, while TH-positive catecholamine neurons were significantly underrepresented. Furthermore, high NMDAR1 expression was also detected in the KS spheroid, similarly to other patients-derived neuronal cultures, denoting high NMDAR1 expression as a general, KS-specific marker. Control and KS neuronal progenitors and neurospheres were exposed to different toxicants (paraquat, rotenone, bardoxolone, and doxorubicin), and dose-response curves were assessed after acute exposure. Differentiation stage and compound-specific differences were detected with KS neurospheres being the most sensitive to paraquat. Altogether this study describes a robust 3D model system expressing the disease-specific markers and recapitulating the characteristic pathophysiological traits. This platform is suitable for testing developing brain-adverse environmental effects interactions, drug development, and screening towards individual therapeutic strategies.
(© 2024. The Author(s).)
Databáze: MEDLINE
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