Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation. Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation

Astrocytes are intimately linked with brain blood vessels, a relationship critical for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation. Overall design: We performed spatial gene expression profiling of astrocytes and microvessels on tissue sections from the developing postnatal mouse cerebral cortex, using the NanoString platform. Three postnatal time points were chosen (P0, P5 and P14) for comparisons. Only wild-type mice were used.

星形胶质细胞与脑血管紧密相连，二者的关联对神经元功能至关重要。然而，在出生后脑发育进程中，介导这些物理与功能联结的胶质细胞因子仍未被探明。本研究通过对出生后前两周小鼠皮层星形胶质细胞的结构与转录变化进行表征，发现通常在损伤时上调、且参与成人脑血管修复的高迁移率族蛋白B1（high-mobility group box 1，Hmgb1）在新生小鼠的星形胶质细胞中高表达，随后迅速下调。出生时对星形胶质细胞特异性敲除Hmgb1，会影响星形胶质细胞的形态与终足定位，改变终足相关蛋白连接蛋白43（connexin43）和水通道蛋白4（aquaporin-4）的分布，诱导星形胶质细胞中与细胞骨架重塑相关的转录变化，并严重破坏内皮超微结构。尽管出生后缺失胶质细胞Hmgb1不会影响血脑屏障或血管生成，但会损害成年小鼠的神经血管耦合能力与行为表现。本研究结果确认，胶质细胞Hmgb1是出生后神经血管胶质成熟过程中的关键调控因子。整体实验设计：本研究采用NanoString平台，对出生后发育中的小鼠大脑皮层组织切片中的星形胶质细胞与微血管进行空间基因表达谱分析。选取三个出生后时间点（P0、P5和P14）开展对比实验，仅使用野生型小鼠。