Intranasal administration of exosomes derived from Wharton's jelly mesenchymal stem cells to treat hypoxic-ischemic encephalopathy of prematurity

Survivors of preterm birth are at risk to develop hypoxic-ischemic encephalopathy (HIE) of prematurity. HIE is characterized by severe neuroinflammation leading to severe long-term disability. In animal models of HIE, Wharton's jelly mesenchymal stem 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 feasibility and the anti-inflammatory effects of intranasally administered WJ-MSC-derived exosomes in an animal model of HIE.

We isolated exosomes from WJ-MSC culture supernatants using serial centrifugation. Consistent with the etiology of HIE in preterm newborns, we introduced brain damage in 2-day old rats with lipopolysaccharide i.p. and unilateral carotid artery cautherization followed by hypoxia. As a treatment, rats received an intranasal administration of exosomes. To evaluate the feasibility of an intranasal exosome administration, we labeled and traced the exosomes inside the rats. To evaluate the anti-inflammatory effects of exosomes, we analyzed pro-inflammatory gene expression using real-time PCR.

Intranasally administered exosomes reached the brain already within 30 min after administration. A small portion of exosomes were detected within the lungs and the GI tract, but no exosomes were found in the spleen, likely excluding systemic absorption. Intranasal administration of exosomes dampened the upregulation of pro-inflammatory genes like tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1b and C-X-C motif chemokine 10 (P < 0.05) after experimental HIE.

Intranasal administration is a minimally invasive approach to deliver WJ-MSC-derived exosomes to the brain and represents a novel cell-free treatment for neuroinflammation after HIE of prematurity.