title: The inhibitory effect of mesenchymal stem cell on blood-brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) are well known having beneficial effects on intracerebral hemorrhage (ICH) in previous studies. The therapeutic mechanisms are mainly to investigate proliferation, differentiation, and immunomodulation. However, few studies have used MSCs to treat blood-brain barrier (BBB) leakage after ICH. The influence of MSCs on the BBB and its related mechanisms were investigated when MSCs were transplanted into rat ICH model in this study.
  
  
  METHODS
  Adult male Sprague-Dawley (SD) rats were randomly divided into sham-operated group, PBS-treated (ICH + PBS) group, and MSC-treated (ICH + MSC) group. ICH was induced by injection of IV collagenase into the rats' brains. MSCs were transplanted intravenously into the rats 2 h after ICH induction in MSC-treated group. The following factors were compared: inflammation, apoptosis, behavioral changes, inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9 (MMP-9), peroxynitrite (ONOO(-)), endothelial integrity, brain edema content, BBB leakage, TNF-α stimulated gene/protein 6 (TSG-6), and nuclear factor-κB (NF-κB) signaling pathway.
  
  
  RESULTS
  In the ICH + MSC group, MSCs decreased the levels of proinflammatory cytokines and apoptosis, downregulated the density of microglia/macrophages and neutrophil infiltration at the ICH site, reduced the levels of iNOS and MMP-9, attenuated ONOO(-) formation, and increased the levels of zonula occludens-1 (ZO-1) and claudin-5. MSCs also improved the degree of brain edema and BBB leakage. The protective effect of MSCs on the BBB in ICH rats was possibly invoked by increased expression of TSG-6, which may have suppressed activation of the NF-κB signaling pathway. The levels of iNOS and ONOO(-), which played an important role in BBB disruption, decreased due to the inhibitory effects of TSG-6 on the NF-κB signaling pathway.
  
  
  CONCLUSIONS
  Our results demonstrated that intravenous transplantation of MSCs decreased the levels of ONOO(-) and degree of BBB leakage and improved neurological recovery in a rat ICH model. This strategy may provide a new insight for future therapies that aim to prevent breakdown of the BBB in patients with ICH and eventually offer therapeutic options for ICH.
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. chen85min@126.com.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. lixifeng_zj@126.com.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Li
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. zhangxin_zj@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. hexuying_zj@126.com.
authors.forename: Xuying
authors.initials: X
authors.lastname: He
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. lailingfeng_zj@163.com.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Lai
authors.affiliation: Department of Neurosurgery, The First People's Hospital of Foshan and Foshan Hospital of Sun Yat Sen University, Foshan, Guangdong, 528000, China. liuyanchao_zj@163.com.
authors.forename: Yanchao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. zhuguohui_zj@163.com.
authors.forename: Guohui
authors.initials: G
authors.lastname: Zhu
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. li88wei_zj@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. li85hui_zj@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. fangqinrui_zj@163.com.
authors.forename: Qinrui
authors.initials: Q
authors.lastname: Fang
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. wangzequn_zj@163.com.
authors.forename: Zequn
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. duanchuanzhi_zj@126.com.
authors.forename: Chuanzhi
authors.initials: C
authors.lastname: Duan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000209:etiology; D015815:Cell Adhesion Molecules / Q000627:therapeutic use; D002543:Cerebral Hemorrhage / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; C513056:Tnfaip6 protein, rat; D030421:Peroxynitrous Acid; D052247:Nitric Oxide Synthase Type II; D020780:Matrix Metalloproteinase 9