Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

Abstract

Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating the microglial reaction in the peri-infarct cortex.

Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs

“…We did not see significant differences in carotid blood flow (CBF; as a surrogate for cerebral blood flow) across the lamb groups during the study, although it is interesting that CBF remained highest in the AGA group and lowest in the FGR group, while CBF in the FGR+UCBC animals was midway between the two. Previous studies in rodent models of stroke report different findings on the effects of UCBCs, either having no effect or causing transient improvement in cerebral blood flow [39,40]. In any case, we did not find that CBF was adversely affected in FGR lambs after birth, at least not during the 24 h of our study.…”

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“…Neonatal arterial ischemic stroke is a common cause of spastic hemiplegia in patients with CP, affecting 1 in every 3,500 to 7,700 neonates [39]. Neonates with stroke may exhibit features similar to f, but therapeutic hypothermia is proven to be not as effective for patients with neonatal stroke as it is in HIE [39].…”

“…Neonatal arterial ischemic stroke is a common cause of spastic hemiplegia in patients with CP, affecting 1 in every 3,500 to 7,700 neonates [39]. Neonates with stroke may exhibit features similar to f, but therapeutic hypothermia is proven to be not as effective for patients with neonatal stroke as it is in HIE [39]. Intravenous administration of UC-MSCs improves damage via attenuating reactive gliosis and hypomyelination in a neonatal mouse model of intraventricular hemorrhage (IVH) [39].…”

“…Neonates with stroke may exhibit features similar to f, but therapeutic hypothermia is proven to be not as effective for patients with neonatal stroke as it is in HIE [39]. Intravenous administration of UC-MSCs improves damage via attenuating reactive gliosis and hypomyelination in a neonatal mouse model of intraventricular hemorrhage (IVH) [39]. There are no studies on UC-MSC in a neonatal stroke model; a new study, therefore, examined the safety and efficiency of intravenously administered human umbilical cord-derived MSCs in neonatal stroke mice [39].…”

“…Human umbilical cord tissues were obtained from women who had cesarean sections [39]. Subjects of the study were female and male postnatal day 12 (P12) pups (n = 90), thought to be equivalents to full-term human newborns at postnatal day 0 [39].…”