Fibroblasts repair blood-brain barrier damage and hemorrhagic brain injury via TIMP2.
Fibroblasts repair blood-brain barrier damage and hemorrhagic brain injury via TIMP2.
复制标题
成纤维细胞通过TIMP2修复血脑屏障损伤和出血性脑损伤。
DOI：
10.1016/j.celrep.2022.111709
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发表时间：
2022-11-22
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
成纤维细胞在脑出血(ICH)中的作用仍不清楚。通过靶向成纤维细胞特异性标记物COL1α1，我们产生了去除COL1α1+成纤维细胞的小鼠。这些突变体表现出血脑屏障损伤加剧，损伤体积扩大，神经功能恶化，突显了Col1α1+成纤维细胞在脑出血中的有利作用。与这些发现相呼应的是，在体外脑出血模型中，成纤维细胞显著降低内皮通透性。接下来，我们证明成纤维细胞主要通过上调紧密连接蛋白而不影响跨细胞相关蛋白来促进脑出血血脑屏障的完整性，这表明是一种旁细胞机制而不是跨细胞机制。随后的一项机制研究发现，成纤维细胞的血脑屏障保护作用部分是由TIMP金属肽酶抑制物2(TIMP2)介导的。此外，我们发现外源TIMP2可以减轻脑出血后这些突变体的血脑屏障破坏。提示COL1α1+成纤维细胞以TIMP2依赖的方式通过细胞旁途径修复脑出血血脑屏障损伤，COL1α1+成纤维细胞和TIMP2可能是脑出血治疗的靶点。Xu等人。探讨COL1、α、1+成纤维细胞在脑出血中的功能意义。结果表明，COL1、α、1+成纤维细胞的消融通过旁细胞机制加重出血性脑损伤和血脑屏障损伤。他们进一步证明，COL1α1+成纤维细胞部分通过TIMP2发挥这一有益功能。
The function of fibroblasts in intracerebral hemorrhage (ICH) remains elusive. By targeting Col1α1, a fibroblast-specific marker, we generate mice with ablated Col1α1+ fibroblasts. These mutants show exacerbated blood-brain barrier (BBB) damage, enlarged injury volume, and worse neurological function, highlighting a beneficial role of Col1α1+ fibroblasts in ICH. Echoing these findings, fibroblasts significantly decrease endothelial permeability in an in vitro ICH model. Next, we demonstrate that fibroblasts promote BBB integrity in ICH mainly via up-regulating tight junction proteins without affecting transcytosis-associated proteins, indicating a paracellular rather than transcellular mechanism. A subsequent mechanistic study reveals that the BBB-protective effect of fibroblasts is partially mediated by TIMP metallopeptidase inhibitor 2 (TIMP2). Furthermore, we find that exogenous TIMP2 attenuates BBB disruption in these mutants after ICH. These results suggest that Col1α1+ fibroblasts repair BBB damage in ICH via the paracellular pathway in a TIMP2-dependent manner, and that Col1α1+ fibroblasts and TIMP2 may be targeted in ICH treatment. Xu et al. investigate the functional significance of Col1α1+ fibroblasts in intracerebral hemorrhage. They show that ablation of Col1α1+ fibroblasts exacerbates hemorrhagic brain injury and blood-brain barrier damage through the paracellular mechanism. They further demonstrate that Col1α1+ fibroblasts exert this beneficial function partially via TIMP2.
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DOI：
10.1007/978-1-4939-3670-0_9
发表时间：
2016
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Kumar M;Nerurkar VR
通讯作者：
Nerurkar VR
影响因子：
9.3
作者：
Gautam, Jyoti;Xu, Lingling;Yao, Yao
通讯作者：
Yao, Yao
影响因子：
48
作者：
Buch, T;Heppner, FL;Waisman, A
通讯作者：
Waisman, A
影响因子：
20.3
作者：
Kim, Soo Hyeon;Cho, Young-Rak;Seo, Dong-Wan
通讯作者：
Seo, Dong-Wan
影响因子：
11.8
作者：
DeSisto J;O'Rourke R;Jones HE;Pawlikowski B;Malek AD;Bonney S;Guimiot F;Jones KL;Siegenthaler JA
通讯作者：
Siegenthaler JA