Pedrosa Erika, Sandler Vladislav, Shah Abhishek, Carroll Reed, Chang Chanjung, Rockowitz Shira, Guo Xingyi, Zheng Deyou, Lachman Herbert M
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York 10416, USA.
J Neurogenet. 2011 Oct;25(3):88-103. doi: 10.3109/01677063.2011.597908. Epub 2011 Jul 29.
Induced pluripotent stem cell (iPSC) technology has the potential to transform regenerative medicine. It also offers a powerful tool for establishing in vitro models of disease, in particular, for neuropsychiatric disorders where live human neurons are essentially impossible to procure. Using iPSCs derived from three schizophrenia (SZ) patients, one of whom has 22q11.2del (velocardiofacial syndrome; VCFS), the authors developed a culture system to study SZ on a molecular and cellular level. SZ iPSCs were differentiated into functional, primarily glutamatergic neurons that were able to fire action potentials after ∼8 weeks in culture. Early differentiating neurons expressed a number of transcription factors/chromatin remodeling proteins and synaptic proteins relevant to SZ pathogenesis, including ZNF804A, RELN, CNTNAP2, CTNNA2, SMARCA2, and NRXN1. Although a small number of lines were developed in this preliminary study, the SZ line containing 22q11.2del showed a significant delay in the reduction of endogenous OCT4 and NANOG expression that normally occurs during differentiation. Constitutive expression of OCT4 has been observed in Dgcr8-deficient mouse embryonic stem cells (mESCs); DGCR8 maps to the 22q11.2-deleted region. These findings demonstrate that the method of inducing neural differentiation employed is useful for disease modeling in SZ and that the transition of iPSCs with 22q11.2 deletions towards a differentiated state may be marked by subtle changes in expression of pluripotency-associated genes.
诱导多能干细胞（iPSC）技术具有变革再生医学的潜力。它还为建立疾病的体外模型提供了一个强大的工具，特别是对于那些几乎无法获取活人神经元的神经精神疾病而言。作者利用来自三名精神分裂症（SZ）患者（其中一名患有22q11.2缺失[心面综合征；VCFS]）的iPSC，开发了一种培养系统，用于在分子和细胞水平上研究SZ。SZ iPSC分化为功能性的、主要为谷氨酸能的神经元，这些神经元在培养约8周后能够产生动作电位。早期分化的神经元表达了许多与SZ发病机制相关的转录因子/染色质重塑蛋白和突触蛋白，包括ZNF804A、RELN、CNTNAP2、CTNNA2、SMARCA2和NRXN1。尽管在这项初步研究中只建立了少数细胞系，但含有22q11.2缺失的SZ细胞系在分化过程中内源性OCT4和NANOG表达的降低出现了显著延迟。在Dgcr8缺陷的小鼠胚胎干细胞（mESC）中观察到OCT4的组成性表达；DGCR8定位于22q11.2缺失区域。这些发现表明，所采用的诱导神经分化方法对SZ的疾病建模有用，并且具有22q11.2缺失的iPSC向分化状态的转变可能以多能性相关基因表达的细微变化为标志。
