Abstract
During experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis associated with blood-brain barrier (BBB) disruption, oligodendrocyte precursor cells (OPCs) overexpress proteoglycan nerve/glial antigen 2 (NG2), proliferate, and make contacts with the microvessel wall. To explore whether OPCs may actually be recruited within the neurovascular unit (NVU), de facto intervening in its cellular and molecular composition, we quantified by immunoconfocal morphometry the presence of OPCs in contact with brain microvessels, during postnatal cerebral cortex vascularization at postnatal day 6, in wild-type (WT) and NG2 knock-out (NG2KO) mice, and in the cortex of adult naïve and EAE-affected WT and NG2KO mice. As observed in WT mice during postnatal development, a higher number of juxtavascular and perivascular OPCs was revealed in adult WT mice during EAE compared to adult naïve WT mice. In EAE-affected mice, OPCs were mostly associated with microvessels that showed altered claudin-5 and occludin tight junction (TJ) staining patterns and barrier leakage. In contrast, EAE-affected NG2KO mice, which did not show any significant increase in vessel-associated OPCs, seemed to retain better preserved TJs and BBB integrity. As expected, absence of NG2, in both OPCs and pericytes, led to a reduced content of vessel basal lamina molecules, laminin, collagen VI, and collagen IV. In addition, analysis of the major ligand/receptor systems known to promote OPC proliferation and migration indicated that vascular endothelial growth factor A (VEGF-A), platelet-derived growth factor-AA (PDGF-AA), and the transforming growth factor-β (TGF-β) were the molecules most likely involved in proliferation and recruitment of vascular OPCs during EAE. These results were confirmed by real time-PCR that showed Fgf2, Pdgfa and Tgfb expression on isolated cerebral cortex microvessels and by dual RNAscope-immunohistochemistry/in situ hybridization (IHC/ISH), which detected Vegfa and Vegfr2 transcripts on cerebral cortex sections. Overall, this study suggests that vascular OPCs, in virtue of their developmental arrangement and response to neuroinflammation and growth factors, could be integrated among the classical NVU cell components. Moreover, the synchronized activation of vascular OPCs and pericytes during both BBB development and dysfunction, points to NG2 as a key regulator of vascular interactions.
Highlights
Oligodendrocyte precursor cells (OPCs) are proliferating elements of the oligodendroglia lineage that remain in the adult brain at the end of oligodendrogenesis as a unique type of potentially self-renewing glia and generate oligodendrocytes throughout life [1, 2]
OPCs in neurovascular unit constitutively expressed by mature pericytes; nerve/glial antigen 2 (NG2) and platelet-derived growth factor receptor β (PDGFRβ) as markers for activated pericytes; CD45 and Iba1 for revealing monocytes/macrophages, which in pathological contexts could transiently express NG2 [19,20,21]
OPCs immunolocalized by both NG2 and plateletderived growth factor receptor α (PDGFRα), were classified according to their position with regard to the vessel wall, as perivascular (PV), when the cell body was in contact with the vessel wall and juxtavascular (JV), when only the cell processes contacted the vessels; OPCs scattered in the cortex, and virtually not associated with the vessel wall, were classified as parenchymal (Pa) OPCs (Fig 1A–1C)
Summary
Oligodendrocyte precursor cells (OPCs) are proliferating elements of the oligodendroglia lineage that remain in the adult brain at the end of oligodendrogenesis as a unique type of potentially self-renewing glia and generate oligodendrocytes throughout life [1, 2]. The same model of EAE repeated in NG2 knock-out mice leads to a milder disease characterized by a less inflammatory profile of pathogenic Th1 lymphocytes, reduced inflammatory infiltrate, and preserved BBB function [11] Overall, these data suggest that if vascular OPCs are members of the neurovascular unit (NVU), they could be involved in the alteration of BBB function during neuroinflammation, and NG2 could interact with endothelial cells engaging the tight junctions (TJs) in the disease response. These data suggest that if vascular OPCs are members of the neurovascular unit (NVU), they could be involved in the alteration of BBB function during neuroinflammation, and NG2 could interact with endothelial cells engaging the tight junctions (TJs) in the disease response This idea is supported by recent data on OPC/vessel mutual relationships [12, 13] and by growing evidence of the importance of NG2 proteoglycan molecular interactions and biological functions [14, 15]. The results demonstrate that OPCs are a dynamic, integral cell component of the developing and adult NVU, and support the hypothesis of NG2 as the molecule involved in TJ regulation during BBB development and dysfunction
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