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

Unlabelled: 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.

Methods: 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.

Results: 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.

Conclusion: 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.