iPSC-Derived Astrocytes and Neurons Replicate Brain Gene Expression, Epigenetic, Cell Morphology and Connectivity Alterations Found in Autism

• Published in: Cells (Basel, Switzerland) Switzerland), 2024-06, Vol.13 (13), p.1095
• Main Authors: Mostafavi Abdolmaleky, Hamid, Alam, Reza, Nohesara, Shabnam, Deth, Richard C, Zhou, Jin-Rong
• Format: Article
• Language: English
• Subjects: Antibiotics; astrocyte; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Autism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Autistic Disorder - pathology; Blood; Brain; Brain - metabolism; Brain - pathology; Cell culture; Cell Shape; Child; Cytology; DNA methylation; DNA Methylation - genetics; En2 gene; Engrailed-2 protein; Epigenesis, Genetic; epigenetic; Epigenetics; Female; Gene expression; Gene Expression Regulation; Genetic testing; Growth rate; Humans; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Inflammation; Intellectual disabilities; iPSC; Male; Morphology; Neural networks; Neurobiology; neuron; Neurons; Neurons - metabolism; Neurons - pathology; Neurosciences; Nuclear receptors; Nurr1 protein; Oxidative stress; Pathogenesis; Promoter Regions, Genetic - genetics; Promoters; Proteins; Reelin Protein; SIRT1 protein; Stem cells; Transforming growth factor-b1
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13131095

Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging. We used iPSC-derived neurons and astrocytes of patients with autism vs. controls (5/group) to examine whether they replicate the postmortem brain expression/epigenetic alterations of autism. Additionally, DNA methylation of 10 postmortem brain samples (5/group) was analyzed for genes affected in PSC-derived cells. We found hyperexpression of , , and and decreased expression of , , , , , , and in the astrocytes of patients with autism, along with DNA hypomethylation of , , and gene promoters and a decrease in promoter 5-hydroxymethylation in the astrocytes of patients with autism. In neurons, and expression trended alike. While promoter was hypermethylated in neurons, and promoters were hypomethylated and exhibited increased promoter 5-hydroxymethlation. We also found a reduction in neuronal arborization, spine size, growth rate, and migration, but increased astrocyte size and a reduced growth rate in autism. In postmortem brain samples, we found DNA hypomethylation of and promoter regions, but DNA hypermethylation of and promoters in autism. Autism-associated expression/epigenetic alterations in iPSC-derived cells replicated those reported in the literature, making them appropriate surrogates to study disease pathogenesis or patient-specific therapeutics.