Stertz Laura, Di Re Jessica, Pei Guangsheng, Fries Gabriel R, Mendez Emily, Li Shenglan, Smith-Callahan Laura, Raventos Henriette, Tipo Jerricho, Cherukuru Rohan, Zhao Zhongming, Liu Ying, Jia Peilin, Laezza Fernanda, Walss-Bass Consuelo
Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Neuropsychopharmacology. 2021 Feb;46(3):673-682. doi: 10.1038/s41386-020-00924-0. Epub 2020 Dec 7.
Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient's genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate < 0.3), in patients compared to controls. We identified 454 differentially expressed genes in hiPSC-derived neurons, enriched in pathways including phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling, with serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3β, as part of this pathway. We further found that pharmacological inhibition of downstream effectors of the PI3K/GSK3 pathway, SGK1 and GSK3, induced alterations in levels of neurite markers βIII tubulin and fibroblast growth factor 12, with differential effects in patients compared to controls. While demonstrating the utility of hiPSCs derived from multiplex families to identify significant cell-specific gene network alterations in SCZ, these studies support a role for disruption of PI3K/GSK3 signaling as a risk factor for SCZ.
人类诱导多能干细胞（hiPSC）有助于建立考虑患者遗传背景的精神疾病脑细胞模型。在此，我们对来自精神分裂症（SCZ）患者的hiPSC衍生细胞系进行了RNA测序分析研究，其中大多数患者来自哥斯达黎加中央山谷人群隔离区的一个复合家庭。使用标准方法从6名健康对照者和7名SCZ患者中生成了hiPSC、神经前体细胞和皮质神经元。使用Illumina HiSeq 2500获得这些细胞的转录组，并使用DESeq2（|倍数变化|>1.5且错误发现率<0.3）对患者与对照进行差异表达分析。我们在hiPSC衍生的神经元中鉴定出454个差异表达基因，这些基因富集于包括磷酸肌醇3激酶/糖原合酶激酶3（PI3K/GSK3）信号传导在内的通路，血清糖皮质激素激酶1（SGK1）作为糖原合酶激酶3β的抑制剂，是该通路的一部分。我们进一步发现，对PI3K/GSK3通路的下游效应器SGK1和GSK3进行药理学抑制会导致神经突标记物βIII微管蛋白和成纤维细胞生长因子12水平发生改变，患者与对照相比有不同的影响。这些研究在证明来自复合家庭的hiPSC在识别SCZ中显著的细胞特异性基因网络改变方面的实用性的同时，支持PI3K/GSK3信号传导中断作为SCZ危险因素的作用。
