Vascularized Brain Assembloids With Enhanced Cellular Complexity Provide Insights Into the Cellular Deficits of Tauopathy.
Vascularized Brain Assembloids With Enhanced Cellular Complexity Provide Insights Into the Cellular Deficits of Tauopathy.
复制标题
细胞复杂性增强的血管化大脑组合体为了解 Tau 蛋白病的细胞缺陷提供了见解。
DOI：
10.1093/stmcls/sxad086
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Qiang,Liang
中科院分区：
文献类型：
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作者：
Sun,Xiaohuan;Kofman,Simeon;Ogbolu,VictorC;Karch,CelesteM;Ibric,Larisa;Qiang,Liang
先进的技术已经使得能够从人类诱导多能干细胞（hiPSC）（即类器官）工程化自组织三维（3D）细胞结构，其概括了人类中枢神经系统（CNS）的组织发育和功能的一些关键特征。虽然hiPSC衍生的3D CNS类器官有望为研究CNS发育和疾病提供人类特异性平台，但它们中的大多数并不包含所有涉及的细胞类型，包括血管细胞组分和小胶质细胞，限制了它们准确重建CNS环境的能力及其在研究疾病某些方面的实用性。在这里，我们开发了一种新的方法，称为血管化脑胶质细胞，用于构建具有更高水平细胞复杂性的hiPSC衍生的3D CNS结构。这是通过将前脑类器官与常见的骨髓祖细胞和表型稳定的人脐静脉内皮细胞（VeraVecs）整合来实现的，所述细胞可以在无血清条件下培养和扩增。与类器官相比，这些类胶质细胞表现出增强的神经上皮增殖、先进的星形胶质细胞成熟和增加的突触数量。引人注目的是，当与源自同基因hiPSC的类胶质细胞相比时，源自含有tauP301 S突变的hiPSC的类胶质细胞表现出增加的总tau和磷酸化tau水平，沿着更高比例的杆状小胶质细胞样细胞和增强的星形胶质细胞活化。此外，tauP301类磷脂显示出神经炎性细胞因子的改变。这种创新的仿人技术是一种引人注目的概念验证模型，为解开人类大脑错综复杂的复杂性开辟了新的途径，并加速了神经系统疾病有效治疗方法的开发。
Advanced technologies have enabled the engineering of self-organized 3-dimensional (3D) cellular structures from human induced pluripotent stem cells (hiPSCs), namely organoids, which recapitulate some key features of tissue development and functions of the human central nervous system (CNS). While hiPSC-derived 3D CNS organoids hold promise in providing a human-specific platform for studying CNS development and diseases, most of them do not incorporate the full range of implicated cell types, including vascular cell components and microglia, limiting their ability to accurately recreate the CNS environment and their utility in the study of certain aspects of the disease. Here we have developed a novel approach, called vascularized brain assembloids, for constructing hiPSC-derived 3D CNS structures with a higher level of cellular complexity. This is achieved by integrating forebrain organoids with common myeloid progenitors and phenotypically stabilized human umbilical vein endothelial cells (VeraVecs), which can be cultured and expanded in serum-free conditions. Compared with organoids, these assembloids exhibited enhanced neuroepithelial proliferation, advanced astrocytic maturation, and increased synapse numbers. Strikingly, the assembloids derived from hiPSCs harboring the tauP301Smutation exhibited increased levels of total tau and phosphorylated tau, along with a higher proportion of rod-like microglia-like cells and enhanced astrocytic activation, when compared to the assembloids derived from isogenic hiPSCs. Additionally, the tauP301Sassembloids showed an altered profile of neuroinflammatory cytokines. This innovative assembloid technology serves as a compelling proof-of-concept model, opening new avenues for unraveling the intricate complexities of the human brain and accelerating progress in the development of effective treatments for neurological disorders.