Abstract
Peripartum cerebral hypoxia and ischemia, and intrauterine infection and inflammation, are detrimental for the precursor cells of the myelin-forming oligodendrocytes in the prematurely newborn, potentially leading to white matter injury (WMI) with long-term neurodevelopmental sequelae. Previous data show that hypomyelination observed in WMI is caused by arrested oligodendroglial maturation rather than oligodendrocyte-specific cell death. In a rat model of premature WMI, we have recently shown that small extracellular vesicles (sEV) derived from Wharton’s jelly mesenchymal stromal cells (WJ-MSC) protect from myelination deficits. Thus, we hypothesized that sEV derived from WJ-MSC directly promote oligodendroglial maturation in oligodendrocyte precursor cells. To test this assumption, sEV were isolated from culture supernatants of human WJ-MSC by ultracentrifugation and co-cultured with the human immortalized oligodendrocyte precursor cell line MO3.13. As many regulatory functions in WMI have been ascribed to microRNA (miR) and as sEV are carriers of functional miR which can be delivered to target cells, we characterized and quantified the miR content of WJ-MSC-derived sEV by next-generation sequencing. We found that WJ-MSC-derived sEV co-localized with MO3.13 cells within 4 h. After 5 days of co-culture, the expression of myelin basic protein (MBP), a marker for mature oligodendrocytes, was significantly increased, while the oligodendrocyte precursor marker platelet-derived growth factor alpha (PDGFRα) was decreased. Notch and MAPK/ERK pathways known to inhibit oligodendrocyte maturation and differentiation were significantly reduced. The pathway enrichment analysis showed that the miR present in WJ-MSC-derived sEV target genes having key roles in the MAPK pathway. Our data strongly suggest that sEV from WJ-MSC directly drive the maturation of oligodendrocyte precursor cells by repressing Notch and MAPK/ERK signaling.
Highlights
White matter injury (WMI) is the most common cerebral abnormality in premature neonates
It is generally accepted to relate to both fetal cerebral hypoxia and ischemia and intrauterine infection and inflammation causing downstream excitotoxicity and oxidative stress, which are harmful to the maturing myelin-forming oligodendrocyte lineage (Khwaja and Volpe, 2008; Volpe, 2008)
We have recently shown that intranasal administration of small EV (sEV) derived from mesenchymal stromal cell (MSC) isolated from the umbilical cord connective tissue, called Wharton’s jelly (WJ), reduced WMI in a preclinical rat model of premature brain injury (Thomi et al, 2019a)
Summary
White matter injury (WMI) is the most common cerebral abnormality in premature neonates. Thanks to improved peripartum care in preterm birth, the number of newborns affected by the cystic form of WMI, called cystic periventricular leukomalacia (PVL), has become very low nowadays (Hamrick et al, 2004). The non-cystic and mostly diffuse type of cerebral WMI remains predominant in very preterm-born infants (Inder et al, 2003; Hamrick et al, 2004; Horsch et al, 2007). The frequency of preterm WMI, counting both cystic and non-cystic, is 39.6% in infants born before gestational week 28, 27.4% before week 32, and 7.3% before week 37 (RomeroGuzman and Lopez-Munoz, 2017). The pathophysiology of premature WMI is complex. Today no effective therapy for preterm WMI is available
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