脑类器官培养技术进展及其在缺血性脑卒中损伤修复中的应用

doi:10.3877/cma.j.issn.2095-1221.2023.02.009

脑类器官在体外再现了部分大脑区域的生长和发育，并且在不涉及实验伦理问题的前提下，揭示了以往未知的中枢神经系统疾病机制。缺血性脑卒中的致残率和死亡率极高，目前尚无有效治疗手段。干细胞及其衍生的外泌体临床疗效局限，而脑类器官展现出极大的治疗潜能。脑类器官移植治疗能够减少脑损伤面积，改善神经功能，并在一定程度上促进自身的生长。本文综述了脑类器官培养技术的最新进展，对优化其结构和功能复杂性以及延长脑类器官存活时间的培养方法进行归纳总结，探讨了脑类器官移植在缺血性脑卒中后治疗应用，为未来脑类器官的正式应用提供前临床评估。

关键词: 类器官, 缺血性脑卒中, 神经修复, 移植, 再生医学

The cerebral organoid has recapitulated the growth and development of some areas of the brain in vitro and has revealed previously unknown mechanisms of central nervous system diseases without ethical concerns. Ischemic stroke has a high disability and mortality rate, and effective treatments are currently lacking. Although stem cells clinical efficacy and excreted extracellular vesicles are limited, cerebral organoids demonstrate significant therapeutic potential. Intervention with cerebral organoids has reduced the brain damage area, improved nerve function, and to some extent, promoted their growth. In this review, we have summarized the latest advances in cerebral organoid culture technology, described methods to optimize its structure and functional complexity and prolong its survival time, and discussed the use of cerebral organoids as therapeutic transplantation materials and pathological models for ischemic stroke. By summarizing these contents, we aim to provide a preclinical evaluation for future formal applications of cerebral organoids.

Key words: Organoid, Ischemicstroke, Neural repair, Transplantation, Regenerative medicine

图1 脑类器官的构建及优化方案

表1 脑类器官血管化研究

脑类器官细胞来源	脑类器官类型	血管化修饰方法	血管化效应	血管化脑类器官存活天数/最终观察时长	参考文献
hiPSCs	皮质类器官	皮质类器官在发育阶段和血管类器官共培养	类器官中产生可灌注的血管网络	50天以上	[32]
hESCs	神经血管类器官	发育中的血管类器官加入基因修饰的神经元，并移植入小鼠皮下	类器官同时维持神经和血管功能	90天	[36]
hESCs	皮质类器官	含ETV2的慢病毒转染hESC并生成脑类器官	类器官功能更加成熟，内部形成复杂的血管样结构，获得了一定血脑屏障特征	120天	[31]
hESCs	脑类器官	在EB形成期向其中加入血管内皮生长因子，后续补充Wnt7a促使血管进一步成熟	类器官内存在血管内皮细胞分化和一定血脑屏障特，后期血管扩张受限	4个月	[35]
hESCs/ hiPSCs	血管化脑类器官	hESCs与人脐静脉内皮细胞混合培养，并向小鼠脑内移植	血管化的类器官表现出更强大的神经发生，更成熟的神经环路，凋亡率显著下降	233天	[33]
hiPSCs	肿瘤神经球	将中胚层祖细胞定向掺入肿瘤神经球	肿瘤神经球内生成有层次的血管网络，出现典型血管超微结构	280天	[34]

表1 脑类器官血管化研究

脑类器官细胞来源	脑类器官类型	血管化修饰方法	血管化效应	血管化脑类器官存活天数/最终观察时长	参考文献
hiPSCs	皮质类器官	皮质类器官在发育阶段和血管类器官共培养	类器官中产生可灌注的血管网络	50天以上	[32]
hESCs	神经血管类器官	发育中的血管类器官加入基因修饰的神经元，并移植入小鼠皮下	类器官同时维持神经和血管功能	90天	[36]
hESCs	皮质类器官	含ETV2的慢病毒转染hESC并生成脑类器官	类器官功能更加成熟，内部形成复杂的血管样结构，获得了一定血脑屏障特征	120天	[31]
hESCs	脑类器官	在EB形成期向其中加入血管内皮生长因子，后续补充Wnt7a促使血管进一步成熟	类器官内存在血管内皮细胞分化和一定血脑屏障特，后期血管扩张受限	4个月	[35]
hESCs/ hiPSCs	血管化脑类器官	hESCs与人脐静脉内皮细胞混合培养，并向小鼠脑内移植	血管化的类器官表现出更强大的神经发生，更成熟的神经环路，凋亡率显著下降	233天	[33]
hiPSCs	肿瘤神经球	将中胚层祖细胞定向掺入肿瘤神经球	肿瘤神经球内生成有层次的血管网络，出现典型血管超微结构	280天	[34]

表2 生物工程与脑类器官构建研究

支架类型	基质类型	加入组分	生成类器官类型	生长情况	参考文献
静态液滴支架	Matrigel-海藻酸盐融合基质	hiPSCs	中脑类器官	类器官结构随着基质硬度改变	[47]
静态液滴支架	海藻酸盐	hiPSCs	脊髓类器官	与Matrigel神经发生和胶质细胞生成的效率相似，同时减少非特异性标记物的表达	[48]
静态液滴支架	脱细胞猪脑ECM	hESCs	脑类器官	增加了培养环境的稳定性，但功能性人脑特异性蛋白并未保留	[49]
静态液滴支架	明胶甲基丙烯酸酯	神经祖细胞	分化的神经细胞聚合物	促进神经元分化，部分神经干细胞干性保留	[50]
静态碳纤维支架	—	生长阶段的中脑类器官	成熟的中脑类器官	加速类器官生长，延长其培养时间，类器官中多巴胺能神经元比例增加	[51]
静态重组丝微纤维支架	—	hiPSCs	脑类器官	降低类器官间的异质性，降低类器官内的变异性，增强自组织能力，促进氧气和营养物质输送	[52]
微流控设备	Matrigel	hESCs	脑类器官	类器官内缺氧核心减少，类器官之间的异质性降低	[53]
微流控设备	脱细胞人脑组织衍生ECM	生长阶段的脑类器官	成熟的脑类器官	增加类器官的神经元和神经胶质细胞数量，促进神经发生和皮质发育，类器官在分子和功能水平上进一步成熟	[45]
微流控设备	GelTrex	生长阶段的中脑类器官	成熟的中脑类器官	类器官活性提升，核心的凋亡坏死情况明显改善，多巴胺能神经元比例增加	[54]
微流控空心网状设备	EB维持培养基	EB、小胶质细胞	管状人脑类器官	类器官缺氧核心减小，类器官异质性减小，神经发育增强	[55]
微流控设备	Matrigel	生长阶段的脑类器官、周细胞、内皮细胞	神经血管类器官	以出芽的方式在类器官内形成复杂的、有灌注能力的血管网络	[56]
微流控设备	纤维蛋白凝胶	神经干细胞球、人脐静脉内皮细胞	血管化的神经干细胞球	促进神经元生长和神经干细胞分化，减少神经细胞凋亡	[57]

表2 生物工程与脑类器官构建研究

支架类型	基质类型	加入组分	生成类器官类型	生长情况	参考文献
静态液滴支架	Matrigel-海藻酸盐融合基质	hiPSCs	中脑类器官	类器官结构随着基质硬度改变	[47]
静态液滴支架	海藻酸盐	hiPSCs	脊髓类器官	与Matrigel神经发生和胶质细胞生成的效率相似，同时减少非特异性标记物的表达	[48]
静态液滴支架	脱细胞猪脑ECM	hESCs	脑类器官	增加了培养环境的稳定性，但功能性人脑特异性蛋白并未保留	[49]
静态液滴支架	明胶甲基丙烯酸酯	神经祖细胞	分化的神经细胞聚合物	促进神经元分化，部分神经干细胞干性保留	[50]
静态碳纤维支架	—	生长阶段的中脑类器官	成熟的中脑类器官	加速类器官生长，延长其培养时间，类器官中多巴胺能神经元比例增加	[51]
静态重组丝微纤维支架	—	hiPSCs	脑类器官	降低类器官间的异质性，降低类器官内的变异性，增强自组织能力，促进氧气和营养物质输送	[52]
微流控设备	Matrigel	hESCs	脑类器官	类器官内缺氧核心减少，类器官之间的异质性降低	[53]
微流控设备	脱细胞人脑组织衍生ECM	生长阶段的脑类器官	成熟的脑类器官	增加类器官的神经元和神经胶质细胞数量，促进神经发生和皮质发育，类器官在分子和功能水平上进一步成熟	[45]
微流控设备	GelTrex	生长阶段的中脑类器官	成熟的中脑类器官	类器官活性提升，核心的凋亡坏死情况明显改善，多巴胺能神经元比例增加	[54]
微流控空心网状设备	EB维持培养基	EB、小胶质细胞	管状人脑类器官	类器官缺氧核心减小，类器官异质性减小，神经发育增强	[55]
微流控设备	Matrigel	生长阶段的脑类器官、周细胞、内皮细胞	神经血管类器官	以出芽的方式在类器官内形成复杂的、有灌注能力的血管网络	[56]
微流控设备	纤维蛋白凝胶	神经干细胞球、人脐静脉内皮细胞	血管化的神经干细胞球	促进神经元生长和神经干细胞分化，减少神经细胞凋亡	[57]

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Advances in brain organoid culture technology and its application in the repair of ischemic stroke injury

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Advances in brain organoid culture technology and its application in the repair of ischemic stroke injury