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.
Highlights
Neonatal stroke is a common cause of acute neonatal encephalopathy and frequently results in neurological impairments such as cerebral palsy, cognitive disorders, and seizures [1, 2]
We have shown that intravenous administration of UC-mesenchymal stem cells (MSCs) ameliorates injuries via attenuating reactive gliosis and hypomyelination in a neonatal mouse model of intraventricular hemorrhage (IVH) [19]
We demonstrated that intravenous administration of human umbilical cord-derived MSCs (UC-MSCs) following middle cerebral artery occlusion (MCAO) in neonatal mice was safe and attenuated damages in neurodevelopmental behaviors and glial cell reaction after neonatal stroke
Summary
Neonatal stroke is a common cause of acute neonatal encephalopathy and frequently results in neurological impairments such as cerebral palsy, cognitive disorders, and seizures [1, 2]. Neonates with stroke may present features of hypoxic-ischemic encephalopathy (HIE) [5, 6], therapeutic hypothermia has not currently been proven effective for neonatal stroke despite its efficacy in HIE. Most neonatal stroke patients are recognized only retrospectively with emerging seizures or hemiparesis days after birth, the patients are likely to miss the opportunity of receiving acute neuroprotective treatments. There is currently no effective treatment for neonatal stroke. A novel therapeutic strategy to improve the outcome of neonatal stroke is needed
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