Abstract
BackgroundMesenchymal 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.MethodsAdult 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.ResultsIn 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.ConclusionsOur 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.
Highlights
Mesenchymal stem cells (MSCs) are well known having beneficial effects on intracerebral hemorrhage (ICH) in previous studies
The intensity of Evan’s blue determined by spectrofluorometric estimation showed that administration of MSCs reduced blood–brain barrier (BBB) leakage when compared with the PBS-treated group 24 and 72 h after ICH (P < 0.05) (Figure 4)
Cytokine levels detected by enzymelinked immunosorbent assay (ELISA) To further assess the microenvironment in the brain which may closely relate to the BBB disruption, we examined the expression of inflammatory-associated
Summary
Mesenchymal stem cells (MSCs) are well known having beneficial effects on intracerebral hemorrhage (ICH) in previous studies. 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. ICH always has the following features: compression of adjacent brain tissue due to hematoma, reduction of cerebral blood flow, disruption of blood–brain barrier (BBB) function, and increased brain edema, which all contribute to neurological deterioration [2,3]. BBB leakage, which is closely associated with brain edema formation, may cause secondary brain damage in ICH patients and lead to disability or death. Disruption of the BBB is an important pathophysiological change after ICH and contributes to formation of vasogenic brain edema, which plays an important role in secondary neuronal death and neurological dysfunction [6,7]
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