Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Ascorbic Acid Ameliorates Molecular and Developmental Defects in Human Induced Pluripotent Stem Cell and Cerebral Organoid Models of Fragile X Syndrome

ABSTRACT: All samples are 50 day old cerebral organoids differentiated from human iPSCs using human the Lancaster protocol (Lancaster et al Nature Protoc, 2014). 4 samples are wild-type (WT) organoids derived from the iPSC line IPSO; 4 samples are Fragile X Syndrome (FX) organoids derived from the iPSC line FX52 in the presence of 15mM HEPES vehicle (Urbach et al, Cell Stem Cell, 2010). 4 samples are Ascorbic Acid treated FX52 cells differentiated into cerebral organoids (FX +AsA). FX +AsA samples were prepared by exposing FX52 iPSCs to 500uM Ascorbic Acid (+15mM HEPES vehicle) for 6 passages (36 days) as iPSCs and then differentiated into cerebral organoids in the presence of Ascorbic Acid throughout the differentiation protocol. By day 50 of the cererbral organoid protocol all organoids were collected for analysis.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Aseel Gadban

PROVIDER: E-MTAB-14543 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We developed a human cerebral organoid model derived from induced pluripotent stem cells (iPSCs) with targeted genome editing to abolish protein expression of the Contactin Associated Protein-like 2 (CNTNAP2) autism spectrum disorder (ASD) risk gene, mimicking loss-of-function mutations seen in patients. CNTNAP2-/- cerebral organoids displayed accelerated cell cycle, ventricular zone disorganisation and increased cortical folding. Proteomic analysis revealed disruptions in glutamatergic/GABAergic synaptic pathways and neurodevelopment, highlighting increased protein expression of corticogenesis and neurodevelopment-related genes such as Forkhead box protein G1 (FOXG1) and Paired box 6 (PAX6). Transcriptomic analysis revealed differentially expressed genes (DEG) belonging to inhibitory neuron-related gene networks. Interestingly, there was a weak correlation between the transcriptomic and proteomic data, suggesting nuanced translational control mechanisms. Along these lines we find upregulated Protein Kinase B (Akt)/mechanistic target of rapamycin (mTOR) signalling in CNTNAP2-/- organoids. Spatial transcriptomics analysis of CNTNAP2-/- ventricular zones demonstrated pervasive changes in gene expression, particularly in PAX6- cells, implicating upregulation of cell cycle regulation pathways, synaptic and glutamatergic/GABAergic pathways. We noted a significant overlap of all omics datasets with idiopathic ASD (macrocephaly) iPSC-derived telencephalic organoids DEG, where FOXG1 was upregulated, along with aberrant expression of Glutamate decarboxylase 1 (GAD1) and T-Box Brain Transcription Factor 1 (TBR1), suggesting altered GABAergic/glutamatergic neuron development. These findings potentially highlight a shared mechanism in the early cortical development of various forms of ASD, further elucidate the role of CNTNAP2 in ASD pathophysiology and cortical development and pave the way for targeted therapies using cerebral organoids as preclinical models.

Dataset Information

Ascorbic Acid Ameliorates Molecular and Developmental Defects in Human Induced Pluripotent Stem Cell and Cerebral Organoid Models of Fragile X Syndrome

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