Disruption of the blood–brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte endfeet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment and also leads to OPC secretion of Wif1, which interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial–vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available from the corresponding author upon request. R code used for the mRNAseq analysis can be found on the following github page: https://github.com/baranzini-lab/RNAseq_QuantSeq_Fancy. Raw sequence data (fastq) for the mRNAseq data are available on DASH data share (https://doi.org/10.7272/Q63N21KB).
Journal peer review information: Nature Neuroscience thanks Ken Arai, Sarah Kucenas, and other anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This work was supported by the National Natural Science Foundation of China (grant no. 31871045) and the National Science Foundation of Chongqing (grant no. cstc2018jcyjAX0702) to J.N., the US National Institutes of Health (grant no. R01-5R01NS088155) to S.E.B. (S.E.B. is the Heidrich Family and Friends Endowed Chair in Neurology at UCSF), and from the US National Institutes of Health (grant no. 1R01NS097551) to S.P.J.F. S.P.J.F. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society.
Integrated supplementary information
Supplementary Video 1 OPC migrates along a vessel at the edge of lesion. Time-lapse video of acute slice culture of spinal cord dorsal funiculus from 1.5 dpl (days post lesion) lesioned adult NG2creERT:tdTomato, following intracardiac infusion of fluorescein-lectin for vessel labeling. Video shows native tdTomato expression in red and vessels in green. A tdTomato-expressing cell (red) migrates along a small vessel (green, outlined by dotted line) at the very edge of a 1.5 dpl dorsal funiculus lysolecithin spinal cord lesion. Frames are taken at 30-min intervals. Imaging experiments were repeated at least four independent times with similar results.
Supplementary Video 2 OPC moves towards and engages a vessel before migrating along. Time-lapse video of acute slice culture of spinal cord dorsal funiculus from 1.5 dpl (days post lesion) lesioned adult NG2creERT:tdTomato, following intracardiac infusion of fluorescein-lectin for vessel labeling. Video shows native tdTomato expression in red and vessels in green. A tdTomato-expressing cell (red) first moves towards and engages a vessel (green, outlined by dotted line), before migrating along it at the very edge of a 1.5 dpl dorsal funiculus lysolecithin spinal cord lesion. Frames are taken at 20 min intervals. Imaging experiments were repeated at least four independent times with similar results.