Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Neuron. 2018 Jun 27;98(6):1170-1183.e8. doi: 10.1016/j.neuron.2018.05.014. Epub 2018 May 31.
Microglia, the brain's resident macrophages, are dynamic CNS custodians with surprising origins in the extra-embryonic yolk sac. The consequences of their distinct ontogeny are unknown but critical to understanding and treating brain diseases. We created a brain macrophage transplantation system to disentangle how environment and ontogeny specify microglial identity. We find that donor cells extensively engraft in the CNS of microglia-deficient mice, and even after exposure to a cell culture environment, microglia fully regain their identity when returned to the CNS. Though transplanted macrophages from multiple tissues can express microglial genes in the brain, only those of yolk-sac origin fully attain microglial identity. Transplanted macrophages of inappropriate origin, including primary human cells in a humanized host, express disease-associated genes and specific ontogeny markers. Through brain macrophage transplantation, we discover new principles of microglial identity that have broad applications to the study of disease and development of myeloid cell therapies.
小胶质细胞是大脑中的常驻巨噬细胞，是具有惊人起源的中枢神经系统守护者，起源于胚胎外的卵黄囊。它们独特的个体发生的后果尚不清楚，但对理解和治疗脑部疾病至关重要。我们创建了一个大脑巨噬细胞移植系统，以厘清环境和个体发生如何决定小胶质细胞的身份。我们发现供体细胞在缺乏小胶质细胞的小鼠中枢神经系统中广泛定植，即使在暴露于细胞培养环境后，当小胶质细胞被重新放回中枢神经系统时，它们完全恢复了身份。尽管来自多种组织的移植巨噬细胞在大脑中可以表达小胶质细胞基因，但只有来自卵黄囊的细胞才能完全获得小胶质细胞的身份。来源不当的移植巨噬细胞，包括人类化宿主中的原代人类细胞，会表达与疾病相关的基因和特定的个体发生标记。通过大脑巨噬细胞移植，我们发现了小胶质细胞身份的新原则，这些原则广泛应用于疾病研究和髓样细胞治疗的发展。
