Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage

Abstract

Previous studies show that intravascular injection of human bone marrow stromal cells (hBMSCs) significantly improves neurological functional recovery in a rat model of intracerebral hemorrhage (ICH). In the present study, we tested the hypothesis that mannitol improves the efficiency of intraarterial MSC delivery (i.e., fewer injected cells required for therapeutic efficacy) after ICH. There were four post-ICH groups (N=9): group 1, negative control with only intra-arterial injection of 1 million human fibroblasts in phosphate-buffered saline (PBS); group 2, intravenous injection of mannitol alone in PBS (1.5 g/kg); group 3, intra-arterial injection of 1 million hBMSCs alone in PBS; and group 4, intravenous injection of mannitol (1.5 g/kg) in PBS followed by intra-arterial injection of 1 million hBMSCs in PBS. Group 4 exhibited significantly improved neurological functional outcome as assessed by neurological severity score (NSS) and corner test scores. Immunohistochemical staining of group 4 suggested increased synaptogenesis, proliferating immature neurons, and neuronal migration. The number of hBMSCs recruited to the injured region increased strikingly in group 4. Tissue loss was notably reduced in group 4. In summary, the beneficial effects of intra-arterial infusion of MSCs are amplified with intravenous injection of mannitol. Preadministration of mannitol significantly increases the number of hBMSCs located in the ICH region, improves histochemical parameters of neural regeneration, and reduces the anatomical and pathological consequences of ICH.

Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery

“…Probably, the contralateral turning is caused by the almost selective cortical lesion site in our model, whereas proximal MCAO induces cortical and striatal lesions. In accordance with this hypothesis striatal lesions have been shown to induce an ipsilateral turning in the corner test (Seyfried et al, 2008). The opposite direction of the turning may be due to an over-compensatory mechanism in pdMCAO as compared to proximal MCAO.…”

Stem cell therapy in intracerebral hemorrhage rat model

“…Many stem cell administration routes have been tested, but it remains unclear which is the best option. Findings in ICH model support that cervical vein delivery is inefficient [133] , whereas good outcomes were already observed following stem cell delivery in brain parenchyma [66,111,[113][114][115][116]121,126,[134][135][136][137] , lateral ventricle [120,133] , tail vein [117,119,122,[124][125][126]138,139] , and carotid artery [133,140,141] . However, each one of these alternatives has drawbacks.…”

“…Also working with NSCs, other group tested the effects of different carotid artery injection times. Acute phase delivery, in this case, returned the worst therapeutic effects [140] . In late transplantation studies, intracerebral stem cell implantation was performed only two months after ictus.…”

“…As stated in previous sections, different stem cell types have different attributes, and knowledge is in its youth about how all these divergences may affect ICH outcome. Bao et al [113] Col Ⅶ hBMSC (Flk-1+) 24 h 2 × 10 5 15 BP Chen et al [120] Col Ⅳ ASC 48 h 3 × 10 6 10 LV Fatar et al [112] Col Ⅳ hASC 24 h 3 × 10 6 500 TV Jeon et al [110] Col Ⅶ ASC extract 1 h --IP Jeong et al [138] Col Ⅳ hNSC 24 h 5 × 10 6 500 TV Kim et al [125] Col Ⅶ hASC 24 h 3 × 10 6 2000 TV Lee et al [126] Col Ⅶ hNSC 2 h; 24 h 5 × 10 6 (TV); 1 × 10 6 (IC) 500 (TV); 2 (BP) TV; BP Li et al [139] Col Ⅶ NSC 2 h; 7 h; 14 h; 21 h; 27 h 4 × 10 6 400 CA Liang et al [114] Col Ⅳ BMSC 24 h 1 × 10 6 10 BP Liao et al [66] Col Ⅶ hUCSC 24 h 2 × 10 5 10 BP Nan et al [158] Col Ⅶ hUCB 24 h 2.4 × 10 6 -3.2 × 10 6 500 SV Otero et al [134] Col Ⅳ BMSC 72 h 2 × 10 6 10 BP Otero et al [115] Col Ⅳ BMSC 2 m 5 × 10 6 15 BP Otero et al [111] Col Ⅳ BMSC 2 h 2 × 10 6 15 BP Qin et al [116] Col Ⅶ iPSC 24 h 2 × 10 6 10 BP Qin et al [135] Col Ⅶ iPSC 24 h 1 × 10 6 10 BP Seghatoleslam et al [124] Col [140] ABI BMSC 24 h 1 × 10 6 100 CA Seyfried et al [122] ABI BMSC 24 h 5 × 10…”

Delivery of stem cells to the brain using MRIgFUS

“…hippocampus in the left (targeted) hemisphere. This specificity makes MRIgFUS superior to other types of BBB disrupting agents which cause widespread BBB permeabilization and have had limited success in stem cell transplantation [12][13]. Furthermore, by delivering the cells directly to the region of interest, the distance the stem cells have to migrate in vivo is minimized.…”