Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.

小胶质细胞是一种专门存在于大脑中的巨噬细胞，在大脑发育、体内平衡和疾病中发挥着至关重要的作用。然而，到目前为止，模拟人脑环境和小胶质细胞之间相互作用的能力受到严重限制。为了克服这些限制，我们开发了一种体内异种移植方法，使我们能够研究功能成熟的人类小胶质细胞（hMG），这些神经胶质细胞在生理相关的血管化免疫功能人脑类器官（iHBO）模型中运作。我们的数据表明，类器官驻留的 hMG 获得了与体内对应物非常相似的人类特异性转录组特征。体内双光子成像揭示 hMG 积极参与监视人脑环境，对局部损伤做出反应，并对全身炎症信号做出反应。最后，我们证明，这里开发的移植 iHBO 为研究健康和疾病中的功能性人类小胶质细胞表型提供了前所未有的机会，并为患有大头畸形的自闭症患者特定模型中大脑环境诱导的免疫反应提供了实验证据。