血管化脑类器官的构建策略和挑战
作者:
作者单位:

天津大学医学工程与转化医学研究院,天津 300072

作者简介:

通讯作者:

中图分类号:

基金项目:

国家重点研发计划(2024YFB4707700)和国家自然科学基金(82171861)资助项目。


Construction Strategies and Challenges of Vascularized Brain Organoids
Author:
Affiliation:

Institute of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China

Fund Project:

This work was supported by grants from National Key Research and Development Program (2024YFB4707700) and The National Natural Science Foundation of China (82171861).

  • 摘要
  • |
  • 图/表
  • |
  • 访问统计
  • |
  • 参考文献
  • |
  • 相似文献
  • |
  • 引证文献
  • |
  • 资源附件
  • |
  • 文章评论
    摘要:

    脑类器官是在体外培养的由多能干细胞(pluripotent stem cells,PSCs)自组织形成的三维(three-dimensional,3D)神经培养物。相比传统二维(two-dimensional,2D)神经细胞培养,脑类器官能够更真实地模拟人脑细胞多样性、3D组织结构、神经网络功能活动等,且克服了动物模型在遗传背景和脑结构特征上与人脑的差异,在重现人脑特异性发育过程、病理特征以及药物反应等方面展现出独特优势,为研究人脑发育和神经系统疾病提供了重要模型。然而,传统脑类器官缺乏功能性脉管系统,导致中心区域氧气和营养物质供应不足,限制了其长期培养和功能成熟,且缺乏神经-血管早期相互作用限制了脑类器官准确建模人脑。近年来,血管化技术的引入显著改善了脑类器官的生理相关性。利用生物学方法(通过内皮细胞共培养、中胚层和外胚层共分化、血管类器官融合,在脑类器官中搭建静态血管网络)、组织工程技术(如通过微流控系统构建动态灌注血管网络,或通过3D打印技术构建人工血管网络)以及在体移植技术(借助宿主血管网络浸润形成具有真实血流灌注的功能性血管网络),研究者们成功构建了多种血管化脑类器官模型。这些模型不仅改善了脑类器官内部缺氧问题,促进其长期培养和成熟,还重建了神经血管单元,模拟了血脑屏障雏形,为研究神经血管疾病和药物测试等提供了高生理相关性平台。然而,实现长期连续功能灌注以及维持血管结构和功能成熟仍是该领域的主要挑战。本文系统总结了人神经血管发育过程和血管化脑类器官的构建策略,并进一步对不同血管化方法进行比较分析以突出其各自的优势和局限性。此外,本文总结了当前脑类器官血管化技术面临的主要挑战,并对其中存在的具体难点进行了讨论。最后,对其在疾病建模和药物测试中的巨大应用前景进行了阐述,讨论了当前血管化脑类器官研究中存在的主要争议和未解决的问题,并对未来研究的可能方向进行了展望。

    Abstract:

    Brain organoids are three-dimensional (3D) neural cultures that self-organize from pluripotent stem cells (PSCs) cultured in vitro. Compared with traditional two-dimensional (2D) neural cell culture systems, brain organoids demonstrate a significantly enhanced capacity to faithfully replicate key aspects of the human brain, including cellular diversity, 3D tissue architecture, and functional neural network activity. Importantly, they also overcome the inherent limitations of animal models, which often differ from human biology in terms of genetic background and brain structure. Owing to these advantages, brain organoids have emerged as a powerful tool for recapitulating human-specific developmental processes, disease mechanisms, and pharmacological responses, thereby providing an indispensable model for advancing our understanding of human brain development and neurological disorders. Despite their considerable potential, conventional brain organoids face a critical limitation: the absence of a functional vascular system. This deficiency results in inadequate oxygen and nutrient delivery to the core regions of the organoid, ultimately constraining long-term viability and functional maturation. Moreover, the lack of early neurovascular interactions prevents these models from fully recapitulating the human brain microenvironment. In recent years, the introduction of vascularization strategies has significantly enhanced the physiological relevance of brain organoid models. Researchers have successfully developed various vascularized brain organoid models through multiple innovative approaches. Biological methods, for example, involve co-culturing brain organoids with endothelial cells to induce the formation of static vascular networks. Alternatively, co-differentiation strategies direct both mesodermal and ectodermal lineages to generate vascularized tissues, while fusion techniques combine pre-formed vascular organoids with brain organoids. Beyond biological approaches, tissue engineering techniques have played a pivotal role in promoting vascularization. Microfluidic systems enable the creation of dynamic, perfusable vascular networks that mimic blood flow, while 3D printing technologies allow for the precise fabrication of artificial vascular scaffolds tailored to the organoid’s architecture. Additionally, in vivo transplantation strategies facilitate the formation of functional, blood-perfused vascular networks through host-derived vascular infiltration. The incorporation of vascularization has yielded multiple benefits for brain organoid models. It alleviates hypoxia within the organoid core, thereby improving cell survival and supporting long-term culture and maturation. Furthermore, vascularized organoids recapitulate critical features of the neurovascular unit, including the early structural and functional characteristics of the blood-brain barrier. These advancements have established vascularized brain organoids as a highly relevant platform for studying neurovascular disorders, drug screening, and other applications. However, achieving sustained, long-term functional perfusion while preserving vascular structural integrity and promoting vascular maturation remains a major challenge in the field. In this review, we systematically outline the key stages of human neurovascular development and provide a comprehensive analysis of the various strategies employed to construct vascularized brain organoids. We further present a detailed comparative assessment of different vascularization techniques, highlighting their respective strengths and limitations. Additionally, we summarize the principal challenges currently faced in brain organoid vascularization and discuss the specific technical obstacles that persist. Finally, in the outlook section, we elaborate on the promising applications of vascularized brain organoids in disease modeling and drug testing, address the main controversies and unresolved questions in the field, and propose potential directions for future research.

    参考文献
    相似文献
    引证文献
引用本文

陈梦梦,胡楠,鲍双庆,李晓红.血管化脑类器官的构建策略和挑战[J].生物化学与生物物理进展,2025,52(7):1757-1770

复制
相关视频

分享
文章指标
  • 点击次数:
  • 下载次数:
  • HTML阅读次数:
  • 引用次数:
历史
  • 收稿日期:2024-11-25
  • 最后修改日期:2025-04-30
  • 录用日期:2025-04-10
  • 在线发布日期: 2025-04-11
  • 出版日期: 2025-07-28
文章二维码
关闭