Fibroblasts repair blood-brain barrier damage and hemorrhagic brain injury via TIMP2

被引:24
作者
Xu, Lingling [1 ]
Nirwane, Abhijit [1 ]
Xu, Ting [2 ]
Kang, Minkyung [1 ]
Devasani, Karan [1 ]
Yao, Yao [1 ,2 ]
机构
[1] Univ S Florida, Morsani Coll Med, Dept Mol Pharmacol & Physiol, 12901 Bruce B Downs Blvd, MDC 8, Tampa, FL 33612 USA
[2] Univ Georgia, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA
基金
美国国家卫生研究院;
关键词
PLASMINOGEN-ACTIVATOR INHIBITOR-1; INTRACEREBRAL HEMORRHAGE; FIBROTIC SCAR; EXTRACELLULAR-MATRIX; IN-VITRO; REGENERATION; PERMEABILITY; SUPPRESSION; PERICYTES; MODELS;
D O I
10.1016/j.celrep.2022.111709
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The function of fibroblasts in intracerebral hemorrhage (ICH) remains elusive. By targeting Col1a1, a fibro-blast-specific marker, we generate mice with ablated Col1a1+ fibroblasts. These mutants show exacer-bated blood-brain barrier (BBB) damage, enlarged injury volume, and worse neurological function, high-lighting a beneficial role of Col1a1+ 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-associ-ated 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 mu-tants after ICH. These results suggest that Col1a1+ fibroblasts repair BBB damage in ICH via the paracel-lular pathway in a TIMP2-dependent manner, and that Col1a1+ fibroblasts and TIMP2 may be targeted in ICH treatment.
引用
收藏
页数:19
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