Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
Immunity. 2023 Sep 12;56(9):2152-2171.e13. doi: 10.1016/j.immuni.2023.07.016. Epub 2023 Aug 14.
Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.
小胶质细胞表型受大脑环境的高度调控，但指定人类小胶质细胞成熟的转录网络知之甚少。在这里，我们描述了胎儿和出生后人类小胶质细胞的阶段特异性转录组和表观基因组，并在诱导多能干细胞 (iPSC) 衍生的小胶质细胞、大脑类器官和人源化小鼠移植后获得了相应的数据。同时发展了考虑转录因子 (TF) 共表达和增强子活性的计算方法，这些方法允许预测与胎儿和出生后小胶质细胞相关的共享和特定状态的基因调控网络。此外，在将 iPSC 细胞移植到人源化小鼠后，许多人类胎儿到出生后的过渡特征以时间依赖性的方式再现。这些数据和伴随的计算方法将有助于进一步阐明人类小胶质细胞获得阶段特异性和疾病特异性表型的机制。
