Therapeutic Benefits of Mesenchymal Stromal Cells in a Rat Model of Hemoglobin-Induced Hypertensive Intracerebral Hemorrhage

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 anti-inflammation, 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-1β and TNF-α). 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.

Mesenchymal stem cells for hemorrhagic stroke: status of preclinical and clinical research

“…Brain edema after BM-MSC 37,40,56,67 and placenta-derived MSC 41 treatment was significantly decreased by 1–10% following stroke injury compared to non-treated groups. Moreover, BM-MSC therapy prevented the development of post-hemorrhagic hydrocephalus (PHH) after severe IVH, and reduced compression of the periventricular corpus callosum induced by PHH.…”

“…Changes in sensorimotor and mechanosensory function after MSC therapy were assessed by modified Neurologic Severity Scores (mNSS; a composite of motor, sensory, balance and reflex tests), limb motor function and modified-limb placing tests, corner turn tests, rotor rod performance, negative geotaxis tests (for newborn rats), modified Kito Score (neurological deficit score), adhesive removal test, Video-Tracking-Box test, and locomotor function evaluation. MSC therapy following stroke significantly attenuated impairment in these tests when compared to stroke-only control groups, 30,31,33–40,43–45,48,51,52,56–59,61,64–66 except for Seyfried and colleagues who report no functional improvements in NSS and corner turn tests when rats were treated with 1 million BM-MSCs, 24 h post-ICH. 32 In contrast, the same group had previously reported significant improvements in NSS and corner turn tests in rats treated with 3, 5, and 8 million BM-MSCs.…”

“…51 Sprague-Dawley rats were the most commonly used, followed by Wistar rats, and two separate studies used the spontaneously hypertensive rat (SHR) model, which would seem well-suited for a cerebral hemorrhage model as hypertension is the primary risk factor of human intracerebral hemorrhage. 40,52 All rat model-based papers investigated MSC treatment across groups of the same sex, with experiments heavily weighted towards male rats, thus it is not possible to reliably assess whether there are sex differences in response to MSC treatment based on animal model data alone. Studies in mouse and primate models were performed exclusively in male animals.…”

Recent Advances in Stem Cell Research in Subarachnoid Hemorrhage

“…The underlying mechanisms of the beneficial effects of MSCs transplantation on various CNS diseases were not limited to parenchymal cell replacement and proinflammatory cytokine inhibition [59,60]. After transplantation, MSCs have been shown to release neurotrophic factors, such as BNDF, in a paracrine manner, affecting the damage niche surrounding target cells [61].…”

Cell-Based Therapies for Stroke: Promising Solution or Dead End? Mesenchymal Stem Cells and Comorbidities in Preclinical Stroke Research

“…There are currently two studies in SHRs with ICH. In both studies, intravenously (35) or intracerebrally (36) transplanted BMMSCs improved neurological function and integrity of the BBB by preventing extravasation of blood through the endothelium (35, 36), resulting in improvements such as reduced brain edema and decreased cell apoptosis (36).…”