Tegtmeyer Matthew, Liyanage Dhara, Han Yu, Hebert Kathryn B, Pei Ruifan, Way Gregory P, Ryder Pearl V, Hawes Derek, Tromans-Coia Callum, Cimini Beth A, Carpenter Anne E, Singh Shantanu, Nehme Ralda
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Commun. 2025 Jul 9;16(1):6332. doi: 10.1038/s41467-025-61547-x.
Neuropsychiatric disorders remain difficult to treat due to complex and poorly understood mechanisms. NeuroPainting is a high-content morphological profiling assay based on Cell Painting and optimized for human stem cell-derived neural cell types, including neurons, progenitors, and astrocytes. The assay quantifies over 4000 features of cell structure and organelle organization, generating a dataset suitable for phenotypic screening in neural models. Here, we show that, in studies of the 22q11.2 deletion-a strong genetic risk factor for schizophrenia-we observe cell-type-specific effects, particularly in astrocytes, including mitochondrial disruption, altered endoplasmic reticulum organization, and cytoskeletal changes. Transcriptomic analysis shows reduced expression of cell adhesion genes in deletion astrocytes, consistent with post-mortem brain data. Integration of RNA and morphology data suggests a link between adhesion gene dysregulation and mitochondrial abnormalities. These results illustrate how combining image-based profiling with gene expression analysis can reveal cellular mechanisms associated with genetic risk in neuropsychiatric disease.
由于机制复杂且了解不足，神经精神疾病仍然难以治疗。NeuroPainting是一种基于细胞绘画的高内涵形态学分析方法，并针对人干细胞衍生的神经细胞类型（包括神经元、祖细胞和星形胶质细胞）进行了优化。该分析方法可量化细胞结构和细胞器组织的4000多个特征，生成适合在神经模型中进行表型筛选的数据集。在这里，我们表明，在对22q11.2缺失（精神分裂症的一个强大遗传风险因素）的研究中，我们观察到细胞类型特异性效应，特别是在星形胶质细胞中，包括线粒体破坏、内质网组织改变和细胞骨架变化。转录组分析显示缺失星形胶质细胞中细胞粘附基因的表达降低，这与死后大脑数据一致。RNA和形态学数据的整合表明粘附基因失调与线粒体异常之间存在联系。这些结果说明了将基于图像的分析与基因表达分析相结合如何能够揭示与神经精神疾病遗传风险相关的细胞机制。
