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- W4387496948 abstract "The prevalence of psychiatric and mental health disorders, including anxiety disorders, major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ) and others, increases with age. While most prior studies have focused on neuronal dysfunction, more recently, the role of glial cells in psychiatric disorders has gained traction. Evidence indicates enriched upregulation in astrocyte-related genes in SCZ, BD and MDD, suggesting that perturbation of astrocyte functionality, including synaptic pruning and neuroinflammation may play a key role in such disorders. However, current astrocyte cell models, such as those differentiated from induced pluripotent stem cells, exhibit fetal-like gene expression signatures, therefore lacking the ability to capture age-associated progression of psychiatric disorders. Since most psychiatric disorders have an age-of-onset in adolescence or adulthood, in vitro astrocyte models that recapitulate an aged phenotype will advance the field. Prior research in neurons has demonstrated that age-associated methylome and transcriptome patterns are retained following direct conversion of fibroblasts, which bypasses the stem-cell state. Although a similar strategy has been attempted for astrocytes using embryonic fibroblasts, these methods have been inefficient for the conversion of adult fibroblasts. We have developed an efficient direct conversion strategy employing a combination of small molecules to induce trans-differentiation of human adult fibroblasts to astrocytes and assessed gene expression and functional phenotypes. Future analyses will focus on DNA methylation profiles and further validation of an aged phenotype. We demonstrate that this method produces mature GFAP+/S100B+ cells at high efficiency (∼40-45%) that are enriched for markers of astrocyte functionality, including ion-channel buffering, gap-junction communication and glutamate uptake; and that these cells exhibit astrocyte-like calcium signaling and neuroinflammatory phenotypes. RNA-Seq analysis indicates an adult rather than fetal astrocytic gene expression signature. Fibroblast-derived astrocytes show higher relative expression of forebrain-specific markers as compared to hindbrain, ventral, or spinal cord markers, suggesting that the astrocytes generated by this protocol potentially resemble a forebrain-specific cortical astrocyte subpopulation. Our method to generate fibroblast-derived induced astrocytes, will provide a useful tool for understanding age-associated disease processes, complementing existing in vitro models, to better understand the role of astrocytes in age-related brain disorders, including mental illness." @default.
- W4387496948 created "2023-10-11" @default.
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- W4387496948 date "2023-10-01" @default.
- W4387496948 modified "2023-10-12" @default.
- W4387496948 title "T5. NEXT GENERATION DISEASE MODELING FOR PSYCHIATRIC DISORDERS: AN ASTROCYTIC AGE-IN-A-DISH MODEL" @default.
- W4387496948 doi "https://doi.org/10.1016/j.euroneuro.2023.08.295" @default.
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