Embryonic Microglia Derive from Primitive Macrophages and Are Replaced by cmyb-Dependent Definitive Microglia in Zebrafish
Embryonic Microglia Derive from Primitive Macrophages and Are Replaced by cmyb-Dependent Definitive Microglia in Zebrafish
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DOI：
10.1016/j.celrep.2018.05.066
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发表时间：
2018-07-03
期刊：
影响因子：
8.8
通讯作者：
Wittamer, Valerie
中科院分区：
文献类型：
--
作者：
Ferrero, Giuliano;Mahony, Christopher B.;Wittamer, Valerie
小胶质细胞是中枢神经系统的巨噬细胞，是多种神经系统疾病治疗干预的主要靶点。然而，利用患者来源的诱导多能干细胞在体外产生小胶质样细胞的有效重编程方案，需要对指导小胶质细胞命运的细胞和分子事件有精确的了解。这仍然是一个挑战，因为小胶质细胞在胚胎发生过程中的发育起源是有争议的。在这里，利用斑马鱼的遗传追踪，我们发现原始巨噬细胞是胚胎小胶质细胞的独特来源。我们还证明了这个初始群体是短暂的，原始小胶质细胞后来被持续整个成年期的确定小胶质细胞所取代。成体波起源于cmyb依赖性造血干细胞。总的来说，我们的工作挑战了将红髓祖细胞作为唯一和直接的小胶质细胞前体的主流模型，并进一步支持了起源于不同造血前体的多波小胶质细胞的存在。
Microglia, the tissue-resident macrophages of the CNS, represent major targets for therapeutic intervention in a wide variety of neurological disorders. Efficient reprogramming protocols to generate microglia-like cells in vitro using patient-derived induced pluripotent stem cells will, however, require a precise understanding of the cellular and molecular events that instruct microglial cell fates. This remains a challenge since the developmental origin of microglia during embryogenesis is controversial. Here, using genetic tracing in zebrafish, we uncover primitive macrophages as the unique source of embryonic microglia. We also demonstrate that this initial population is transient, with primitive microglia later replaced by definitive microglia that persist throughout adulthood. The adult wave originates from cmyb-dependent hematopoietic stem cells. Collectively, our work challenges the prevailing model establishing erythro-myeloid progenitors as the sole and direct microglial precursor and provides further support for the existence of multiple waves of microglia, which originate from distinct hematopoietic precursors.