Therapeutic Benefits of Mesenchymal Stromal Cells in a Rat Model of Hemoglobin-Induced Hypertensive Intracerebral Hemorrhage
Rui Ding1,4, Chunnan Lin2,4,*, ShanShan Wei3, Naichong Zhang2, Liangang Tang2, Yumao Lin2, Zhijun Chen1,*, Teng Xie1, XiaoWei Chen1, Yu Feng1, and LiHua Wu1
1Department of Neurosurgery, Jingmen No. 1 People's Hospital, Jingmen 448000, Hubei, China, 2Department of Neurosurgery, Maoming People’s Hospital, Maoming 525000, Guangdong, China, 3Department of Hematology, Jingmen No. 1 People's Hospital, Jingmen 448000, Hubei, China, 4These authors contributed equally to this work.
*Correspondence: 470681525@qq.com (CL); 415038939@qq.com (ZC)
Received October 25, 2016; Revised December 29, 2016; Accepted January 9, 2017.; Published online February 13, 2017.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

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ABSTRACT
Previous studies have shown that bone marrow mesenchymal stromal cell (MSC) transplantation significantly improves the recovery of neurological function in a rat model of intracerebral hemorrhage. Potential repair mechanisms involve antiinflammation, anti-apoptosis and angiogenesis. However,
few studies have focused on the effects of MSCs on inducible nitric oxide synthase (iNOS) expression and subsequent peroxynitrite formation after hypertensive intracerebral hemorrhage (HICH). In this study, MSCs were transplanted intracerebrally into rats 6 hours after HICH. The modified neurological severity score and the modified limb placing test were used to measure behavioral outcomes. Blood–brain barrier disruption
and neuronal loss were measured by zonula occludens-1 (ZO-1) and neuronal nucleus (NeuN) expression, respectively. Concomitant edema formation was evaluated by H&E staining and brain water content. The effect of MSCs treatment on neuroinflammation was analyzed by immunohistochemical analysis or polymerase chain reaction of CD68, Iba1, iNOS expression and subsequent peroxynitrite formation, and by an enzyme-linked immunosorbent assay of pro-inflammatory factors (IL-1beta and TNF-alpha). The MSCs-treated HICH group showed better performance on behavioral scores and lower brain water content compared to controls. Moreover, the MSC injection increased NeuN and ZO-1 expression measured by immunochemistry/immunofluorescence. Furthermore, MSCs reduced not only levels of CD68, Iba1 and pro-inflammatory factors, but it also inhibited iNOS expression and peroxynitrite formation in perihematomal regions. The results suggest that intracerebral administration of MSCs accelerates neurological function recovery in HICH rats. This may result from the ability of MSCs to suppress inflammation, at least in part, by inhibiting iNOS expression and subsequent peroxynitrite formation.
Keywords: hypertensive intracerebral hemorrhage, iNOS, mesenchymal stromal cells, ONOO-


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