Anti-Inflammatory Effects of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Perinatal Brain Damage
Gierin Thomi1,2, Valérie Haesler1, Marianne Joerger-Messerli1, Daniel V. Surbek1, Andreina Schoeberlein1 1Department of Obstetrics and Gynecology, Bern University Hospital and Department of BioMedical Research, University of Bern, Switzerland; 2Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland
Preterm birth-related perinatal brain damage is characterized by neuroinflammation and leads to significant long-term morbidity. In animal models of perinatal brain damage, 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 evaluate the anti-inflammatory effects of WJ-MSC-derived exosomes in perinatal brain damage. We isolated exosomes from WJ-MSC culture supernatants using serial centrifugation. In vitro, we stimulated the microglia cell line BV-2 and primary mixed astrocytes and microglia with lipopolysaccharide (LPS) in presence or absence of exosomes. In vivo, we introduced brain damage in 3-day old rat pups with LPS i.p. and unilateral carotid artery cautherization followed by hypoxia (8% O2). Exosomes were labeled with an infrared dye, delivered intranasally and traced inside the animals. We evaluated pro-inflammatory gene expression and cytokine secretion as well as toll like receptor (TLR)-4 signaling activation using real-time PCR, enzyme-linked immunosorbent assay and western blot. Intranasally administered exosomes rapidly translocated to the brain. Exosomes suppressed TLR-4 signaling by preventing NF-B inhibitor alpha (IB) from degradation and preventing extracellular signal-regulated kinases (ERK), p38 mitogen-activated protein kinases (MAPK) and stress-activated protein kinase / c-Jun NH(2)-terminal kinase (SAPK/JNK) from phosphorylation (P<0.01). This dampened the upregulation of pro-inflammatory genes like tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1b, C-X-C motif chemokine 10 (P<0.05) and the secretion of TNF-α. We demonstrated the anti-inflammatory effects of WJ-MSC-derived exosomes in models of perinatal brain damage. Intranasal administration of WJ-MSC-derived exosomes offers an effective cell-free approach for treating perinatal brain damage.
Credits: None available.
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