Abstract
Recent studies have indicated oligodendroglial-vascular crosstalk during brain development, but the underlying mechanisms are incompletely understood. We report that oligodendrocyte precursor cells (OPCs) contact sprouting endothelial tip cells in mouse, ferret, and human neonatal white matter. Using transgenic mice, we show that increased or decreased OPC density results in cognate changes in white matter vascular investment. Hypoxia induced increases in OPC numbers, vessel density and endothelial cell expression of the Wnt pathway targets Apcdd1 and Axin2 in white matter, suggesting paracrine OPC-endothelial signaling. Conditional knockout of OPC Wntless resulted in diminished white matter vascular growth in normoxia, whereas loss of Wnt7a/b function blunted the angiogenic response to hypoxia, resulting in severe white matter damage. These findings indicate that OPC-endothelial cell interactions regulate neonatal white matter vascular development in a Wnt-dependent manner and further suggest this mechanism is important in attenuating hypoxic injury.
Highlights
Oligodendrocytes (OLs) are the myelinating cells of the central nervous system
Evidence That oligodendrocyte precursor cells (OPCs) Physically Interact with Angiogenic Tip Cells in White Matter Previous studies have indicated regional differences in regulation of vascular development coupled to metabolic activity and myelination (Harris and Attwell, 2012; Lam et al, 2010; Paredes et al, 2018)
We first investigated the possibility that OPCs physically interact with sprouting endothelial tip cells in white matter (WM)
Summary
Oligodendrocytes (OLs) are the myelinating cells of the central nervous system. During the process of myelination, developing oligodendrocyte precursors (OPCs) undergo dramatic changes in morphology and size as they differentiate, in some cases, achieving a 7,000-fold increase in membrane volume, to supply hundreds of myelin segments for nerve axons (Baron and Hoekstra, 2010; Webster, 1971). By E10, a ventral periventricular plexus forms and starts to branch into the dorsal telencephalon to join the pial vessels (Vasudevan et al, 2008). This network is refined via EC proliferation, sprouting, branching, vessel regression and stabilization (Carmeliet and Jain, 2011), processes regulated by local secretion of vascular endothelial growth factors (VEGFs), bone morphogenetic proteins (BMPs), Wnts, and axon guidance cues derived from various neural cell types (Adams and Eichmann, 2010; Carmeliet and Jain, 2011; Eichmann and Thomas, 2013). Neuroepithelial Wnt7a/b function has been shown to be essential for embryonic CNS vascular development (Cho et al, 2017; Daneman et al, 2009; Stenman et al, 2008; Zhou et al, 2014)
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