Fate mapping via CCR2-CreER mice reveals monocyte-to-microglia transition in development and neonatal stroke.

Chen, Hong-Ru; Sun, Yu-Yo; Chen, Ching-Wen; Kuo, Yi-Min; Kuan, Irena S; Tiger Li, Zheng-Rong; Short-Miller, Jonah C; Smucker, Marchelle R et al. · Sci Adv · 2020

basic_science · Level V

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Abstract

Whether monocytes contribute to the brain microglial pool in development or after brain injury remains contentious. To address this issue, we generated CCR2-CreER mice to track monocyte derivatives in a tamoxifen-inducible manner. This method labeled Ly6C<sup>hi</sup> and Ly6C<sup>lo</sup> monocytes after tamoxifen dosing and detected a surge of perivascular macrophages before blood-brain barrier breakdown in adult stroke. When dosed by tamoxifen at embryonic day 17 (E17), this method captured fetal hematopoietic cells at E18, subdural Ki67<sup>+</sup> ameboid cells at postnatal day 2 (P2), and perivascular microglia, leptomeningeal macrophages, and Iba1<sup>+</sup>Tmem119<sup>+</sup>P2RY12<sup>+</sup> parenchymal microglia in selective brain regions at P24. Furthermore, this fate mapping strategy revealed an acute influx of monocytes after neonatal stroke, which gradually transformed into a ramified morphology and expressed microglial marker genes (Sall1, Tmem119, and P2RY12) for at least 62 days after injury. These results suggest an underappreciated level of monocyte-to-microglia transition in development and after neonatal stroke.

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