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Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic–Ischemic Brain Injury

1
The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia
2
Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
3
Cerebral Palsy Alliance Research Institute, University of Sydney, Camperdown 2086, Australia
4
Department of Paediatrics, Monash University, Clayton 3168, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(10), 2449; https://doi.org/10.3390/ijms20102449 (registering DOI)
Received: 29 March 2019 / Revised: 15 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
(This article belongs to the Special Issue Stem Cell-Based Therapy)
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Abstract

Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic–ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury. View Full-Text
Keywords: cerebral palsy; cord tissue cells; mesenchymal stem cells; neurodevelopment; perinatal brain injury cerebral palsy; cord tissue cells; mesenchymal stem cells; neurodevelopment; perinatal brain injury
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McDonald, C.A.; Djuliannisaa, Z.; Petraki, M.; Paton, M.C.B.; Penny, T.R.; Sutherland, A.E.; Castillo-Melendez, M.; Novak, I.; Jenkin, G.; Fahey, M.C.; Miller, S.L. Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic–Ischemic Brain Injury. Int. J. Mol. Sci. 2019, 20, 2449.

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