Loss of mural cell-derived laminin aggravates hemorrhagic brain injury
Loss of mural cell-derived laminin aggravates hemorrhagic brain injury
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DOI：
10.1186/s12974-020-01788-3
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发表时间：
2020-04-06
影响因子：
9.3
通讯作者：
Yao, Yao
中科院分区：
文献类型：
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作者：
Gautam, Jyoti;Xu, Lingling;Yao, Yao
壁细胞合成层粘连蛋白并沉积到基膜上。为了研究壁细胞来源的层粘连蛋白的功能，我们产生了一个缺乏壁细胞来源的层粘连蛋白的突变小鼠系（称为PKO）。在之前的研究中，我们发现PKO小鼠在稳态条件下基本正常，但随着年龄的增长（bb0 - 8个月），血脑屏障（BBB）发生了破坏，这表明这些突变体本质上是脆弱的。基于这些发现，我们假设PKO小鼠在病理条件下加重了损伤。方法采用胶原酶诱导的脑出血（ICH）作为损伤模型，研究了PKO小鼠及其野生型幼龄（6-8周）的脑卒中预后，包括血肿体积、神经功能、神经元死亡、血脑屏障完整性、细胞旁/跨细胞转运、炎症细胞浸润和脑含水量。此外，透射电子显微镜（TEM）分析和体外ICH模型研究了潜在的分子机制。结果与年龄匹配的野生型小鼠相比，PKO小鼠的中风结果加重，包括血肿大小增大、神经功能恶化、神经元细胞死亡增加、血脑屏障通透性增强、胞吞增加和炎症细胞浸润增加。这些突变体还表现出不依赖于水通道蛋白-4 （AQP4）的高基线脑含水量。此外，在体外ICH模型中，壁细胞来源的层粘连蛋白显著降低了caveolin-1，而不影响紧密连接蛋白。结论壁细胞源性层粘连蛋白通过降低小泡蛋白-1和胞吞作用减轻脑出血血脑屏障损伤，调节脑水稳态，在脑出血中发挥有益作用。
Background Mural cells synthesize and deposit laminin to the basement membrane. To investigate the function of mural cell-derived laminin, we generated a mutant mouse line lacking mural cell-derived laminin (termed PKO). In a previous study, we showed that the PKO mice were grossly normal under homeostatic condition, but developed blood-brain barrier (BBB) breakdown with advanced age (> 8 months), suggesting that these mutants are intrinsically weak. Based on these findings, we hypothesized that PKO mice have exacerbated injuries in pathological conditions. Methods Using collagenase-induced intracerebral hemorrhage (ICH) as an injury model, we examined various stroke outcomes, including hematoma volume, neurological function, neuronal death, BBB integrity, paracellular/transcellular transport, inflammatory cell infiltration, and brain water content, in PKO mice and their wildtype littermates at young age (6-8 weeks). In addition, transmission electron microscopy (TEM) analysis and an in vitro ICH model were used to investigate the underlying molecular mechanisms. Results Compared to age-matched wildtype littermates, PKO mice display aggravated stroke outcomes, including larger hematoma size, worse neurological function, increased neuronal cell death, enhanced BBB permeability, increased transcytosis, and elevated inflammatory cell infiltration. These mutants also exhibit high baseline brain water content independent of aquaporin-4 (AQP4). In addition, mural cell-derived laminin significantly reduced caveolin-1 without affecting tight junction proteins in the in vitro ICH model. Conclusions These results suggest that mural cell-derived laminin attenuates BBB damage in ICH via decreasing caveolin-1 and thus transcytosis, regulates brain water homeostasis, and plays a beneficial role in ICH.