61: Intranasal administration of exosomes from umbilical cord stem cells to treat perinatal white matter injury

Abstract

Infants born prematurely are at high risk to suffer from perinatal white matter injury. Perinatal white matter injury is characterized by exacerbated neuroinflammation which causes subsequent neurodevelopmental deficits. In animal models of white matter injury, Wharton’s jelly mesenchymal stem/stromal cells (WJ-MSC) derived from umbilical cords can reduce neuroinflammation, in part because they release cell-derived extracellular vesicles like exosomes. We aimed to test the therapeutic potential of intranasally administered WJ-MSC-derived exosomes in an animal model of perinatal white matter injury. We isolated exosomes from WJ-MSC culture supernatants using serial centrifugation. Consistent with the etiology of brain injury in preterm infants, we introduced brain injury in 3-day old rat pups with LPS i.p. and unilateral carotid artery cauterization followed by hypoxia (8% O2). As a treatment, animals received an intranasal administration of infrared dye-labeled exosomes and their distribution was traced with an infrared scanner. After 24 hours, we analyzed neuroinflammation markers using real-time RT-PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). We also tracked the survival of the animals and measured their learning capacity using the Morris water maze assay. Intranasally administered exosomes rapidly translocated to the brain and arrived within 30 min after administration. No exosomes were found in the spleen, most likely excluding systemic absorption. Treated animals exhibited reduced signs of neuroinflammation as the exosomes dampened the upregulation of inflammation related genes such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β (P<0.05), decreased the levels of brain parenchymal pro-inflammatory cytokines TNFα and IL-1β (P<0.001) and prevented white matter microgliosis (P<0.05) 24 hours after experimental white matter injury. Exosome treatment doubled the animal’s survival rate (P=0.003) and increased their learning capacity (P<0.05) one month after white matter injury. The intranasal administration of WJ-MSC-derived exosomes represents a minimally invasive therapy for reducing neuroinflammation in perinatal white matter injury.