An iPSC based humanized mouse model of dysmyelination in schizophrenia

描述(申请人提供)：精神分裂症可能是最具人类特异性的精神病理学。它是最严重和最常见的精神障碍之一，会导致巨大的残疾、痛苦和费用，但对其病因却鲜有人弄清楚。这就是说，精神分裂症对人类的特殊性，以及它经常以较小的形式与 创造力，表明它特别与人类的神经能力有关。然而，自相矛盾的是，基因关联研究强调了少突胶质细胞和白质基因与精神分裂症的关联，而不是人们可能预期的神经元基因，这是人类独有的病理。同样，最近的放射学研究也强调了精神分裂症患者早期出现的髓鞘过少，通常在疾病发作之前很久。这些观察表明，精神分裂症患者神经元组织和神经元结构的异常特征可能源于神经胶质前体和/或少突胶质细胞的病理，祖细胞调节失调、髓鞘功能障碍和神经元的少突胶质细胞支持失败导致发育中断的网络结构。在这项应用中，我们将重点研究OPC和少突胶质细胞在精神分裂症发生中的作用，利用一套新的技术，我们可以培育出嵌合小鼠，其神经胶质细胞群体已经被来自HiPSC的胶质细胞所取代，而HPSC来源的胶质细胞本身来自青少年精神分裂症患者。利用先天少髓鞘寒战小鼠作为宿主，我们可以产生白质胶质细胞和髓鞘几乎完全来自人类的小鼠，用人类细胞完全取代宿主OPC和少突胶质细胞。为了确定这一建议的可行性，我们使用精神分裂症衍生的HiPSC OPC在髓磷脂缺乏的颤抖小鼠中建立了人神经胶质嵌合体。我们发现，由此产生的人类神经胶质嵌合小鼠--通常在新生儿人类OPC移植后很好地形成髓鞘--反而表现出精神分裂症患者特有的髓鞘过少，伴有异常的OPC分散和迁移，同时伴有明显的包膜和膝盖骨髓鞘异常化。在此基础上，我们现在建议研究这些小鼠白质的解剖和转录结构，重点关注它们移植的OPC相对于正常对照HiPSC OPC的分布，以及精神分裂症来源的HiPSC OPC的少突胶质细胞分化和髓鞘形成。然后，我们将研究它们的基因表达模式，在mRNA和miRNA方面，后者以确定精神分裂症来源的HiPSC OPC可能经历的任何更高级别的转录失调。通过提供新的人类神经胶质嵌合模型系统、精神分裂症患者衍生的OPC形式的新细胞试剂以及新的表型特定和疾病相关的基因表达数据库，该项目将提供一套广泛和令人兴奋的新工具、功能和数据库。总之，这些研究应该为我们提供对神经胶质前体细胞和 其衍生的髓鞘在精神分裂症的发病机制中的作用。

DESCRIPTION (provided by applicant): Schizophrenia is perhaps the most human-specific psychopathology. It is one of the most severe - and common - psychiatric disorders, a cause of tremendous disability, distress and expense, and yet little remains clear about its etiology. That said, the specificity of schizophrenia to humans, and its frequent association in lesser forms with creativity, suggest its association with specifically human neural competencies. Paradoxically though, gene association studies have highlighted the association of oligodendrocytic and white matter genes with schizophrenia, rather than the neuronal genes that one might have expected of a pathology so uniquely human. Similarly, recent radiographic studies have highlighted the early appearance of hypomyelination in schizophrenics, often long before disease onset. These observations suggest that the aberrant features of neuronal organization and neuritic structure noted in schizophrenics might derive from glial progenitor and/or oligodendrocytic pathology, with progenitor dysregulation, dysmyelination and failed oligodendrocytic support of neurons yielding a developmentally-disrupted network structure. In this application, we will focus on the roles of OPCs and oligodendroglia in the genesis of schizophrenia, using a novel set of technologies by which we can produce chimeric mice whose glial populations have been largely replaced by hiPSC-derived glia, themselves derived from patients with juvenile-onset schizophrenia. By using congenitally hypomyelinated shiverer mice as hosts, we can generate mice whose white matter glia and myelin are almost entirely of human origin, with complete replacement of host OPCs and oligodendroglia by human cells. To establish the feasibility of this proposal, we established human glial chimeras in myelin-deficient shiverer mice, using schizophrenia-derived hiPSC OPCs. We found that the resultant human glial chimeric mice - which typically myelinate well following neonatal human OPC transplants - instead phenocopied the hypomyelination so characteristic of schizophrenic patients, with aberrant OPC dispersal and migration accompanying overt capsular and callosal dysmyelination. On that basis, we now propose to study the anatomy and transcriptional architecture of the white matter of these mice, focusing on the distribution of their engrafted OPCs relative to normal control hiPSC OPCs, as well as on oligodendrocytic differentiation and myelin formation by schizophrenia-derived hiPSC OPCs. We will then investigate their gene expression patterns, in terms of both mRNA and miRNA, the latter so as to define any higher-order transcriptional dysregulation that may be experienced by the schizophrenia-derived hiPSC OPCs. By providing a new human glial chimeric model system, new cellular reagents in the form of schizophrenic patient-derived OPCs, and new phenotype-specific and disease-associated gene expression databases, this project will make available a broad and exciting new set of tools, capabilities and databases. Together, these studies should provide us great insight into the role of glial progenitor cells and their derived myelin in the pathogenesis of schizophrenia.