Development of Patient-Specific Neurons in Schizophrenia Using Induced Pluripotent Stem Cells
Development of Patient-Specific Neurons in Schizophrenia Using Induced Pluripotent Stem Cells
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DOI：
10.3109/01677063.2011.597908
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发表时间：
2011-10-01
影响因子：
1.9
通讯作者：
Lachman, Herbert M.
中科院分区：
文献类型：
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作者：
Pedrosa, Erika;Sandler, Vladislav;Lachman, Herbert M.
诱导多能干细胞（iPSC）技术有可能改变再生医学。它还提供了一个强大的工具，用于建立体外疾病模型，特别是神经精神疾病，其中活的人类神经元基本上是不可能获得的。使用来自三名精神分裂症（SZ）患者的iPSCs，其中一名患有22q11.2del（velocardiofacial syndrome; VCFS），作者开发了一种培养系统，在分子和细胞水平上研究SZ。SZ iPSC分化成功能性的主要是神经元，其能够在培养类似8周后激发动作电位。早期分化的神经元表达了许多转录因子/染色质重塑蛋白和与SZ发病机制相关的突触蛋白，包括ZNF 804 A、CANN、CNTNAP 2、CTNNA 2、SMARCA 2和NRXN 1。尽管在该初步研究中开发了少量的系，但含有22q11.2del的SZ系显示出在分化期间通常发生的内源性OCT 4和NANOG表达的降低的显著延迟。在Dgcr 8缺陷型小鼠胚胎干细胞（mESC）中观察到OCT 4的组成型表达; DGCR 8定位于22q11.2缺失区。这些发现表明，所采用的诱导神经分化的方法对于SZ中的疾病建模是有用的，并且具有22q11.2缺失的iPSC向分化状态的转变可以通过多能性相关基因表达的细微变化来标记。
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 similar to 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.