Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92696, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92696, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92696, USA.
Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA.
Neuron. 2019 Sep 25;103(6):1016-1033.e10. doi: 10.1016/j.neuron.2019.07.002. Epub 2019 Jul 30.
iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Aβ-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aβ-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically modified microglia.
诱导多能干细胞（iPSC）衍生的小胶质细胞为研究小胶质细胞的内稳态和与疾病相关的炎症反应提供了有力的工具。然而，小胶质细胞对外界环境非常敏感，与大脑分离时会表现出转录组缺陷。此外，物种特异性的遗传变异表明，啮齿动物小胶质细胞不能完全再现人类的情况。为了解决这个问题，我们开发了一种在替代脑环境中研究人类小胶质细胞的方法。将 iPSC 衍生的造血祖细胞移植到人源化免疫缺陷小鼠的出生后大脑中，会导致其在特定环境下分化为小胶质细胞和其他中枢神经系统巨噬细胞，获得体外人类小胶质细胞的基因特征，并对急性和慢性损伤做出反应。最值得注意的是，移植的小胶质细胞对 Aβ 斑块表现出强烈的转录反应，而与鼠类小胶质细胞的反应仅有部分重叠，揭示了新的、人类特异性的 Aβ 反应基因。因此，我们已经证明，这种嵌合模型为研究患者来源和基因修饰的小胶质细胞的体内功能提供了一个强大的新系统。
