Human Wharton’s Jelly Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Drive Oligodendroglial Maturation by Restraining MAPK/ERK and Notch Signaling Pathways

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.

Low-Dose Radiation Can Cause Epigenetic Alterations Associated With Impairments in Both Male and Female Reproductive Cells

“…Also, Hippo signaling cascade was found to be associated with the pubertal development of male reproductive tract and spermatogenesis in sheep ( Zhang et al, 2019 ). MAPK signaling pathway is the key mediator that controls the phosphorylation of many downstream effectors, leading to modulate different cellular functions, including cell proliferation, differentiation, and migration ( Joerger-Messerli et al, 2021 ). Oxidative stress-mediated p38 MAPK signaling pathway was associated with the blood-testis barrier-related junction protein and promoting apoptosis in mice testes ( Huang et al, 2021 ).…”

Effect of Multiple Sclerosis Cerebrospinal Fluid and Oligodendroglia Cell Line Environment on Human Wharton’s Jelly Mesenchymal Stem Cells Secretome

“…There are limited data on the direct interaction between human stem cells and oligodendroglia. A recently published study by Joerger-Messerli provided evidence that human extracellular vesicles derived from WJ-MSCs interacted with the MO3.13 cell line and accelerated their maturation after 5 days of co-culture [54]. In our study, we observed secretion of cytokines/chemokines/growth factors after 2 days of cell-to-cell contact of WJ-MSCs and MO3.13 and showed significant inhibition of MSCs secretory activity, which might be related to initiation of differentiation of MSCs.…”

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

“…The normal expression of OLIG2 contributes to the developmental regulation of oligodendrocytes precursor cells and the early directed differentiation to OLs. OLs are widely distributed in the central nervous system, which contribute to the formation of myelin sheath and could be impaired by neuroinflammation ( Xie et al, 2016 ; Huntemer-Silveira et al, 2020 ; Joerger-Messerli et al, 2021 ). In this study, we confirmed PND increased the expression of WNT10B and β-catenin and decreased the expression of OLIG2.…”