期刊
BRAIN
卷 144, 期 -, 页码 2291-2301出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awab106
关键词
multiple sclerosis; blood-brain barrier; promyelinating drugs; neuroinflammation; RNA sequencing
资金
- National Institutes of Health/National Center for Research Resources [RR18928]
- National Institutes of Health [P41 GM10341]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R35 NS097976]
- National Multiple Sclerosis Society [FG-1708-28925]
- Race to Erase MS Foundation [P0535497]
- National Multiple Sclerosis Society Postdoctoral Fellowship [FG-1708-28925, FG-1507-05496]
- UCSF Immunology National Institutes of Health/National Institute of Allergy and Infectious Diseases [T32AI007334]
- Berkelhammer Award for Excellence in Neuroscience
- Race to Erase MS Young Investigator Award
- American Heart Association Scientist Development Grant [16SDG30170014]
- Simon Family Trust
- Dagmar Dolby Family Fund
- Conrad N. Hilton Foundation [17348]
- Department of Defense [MS160082]
In neuroinflammatory lesions, extrinsic inhibitors such as fibrinogen lead to clustering of oligodendrocyte precursor cells and hinder remyelination, but blocking the bone morphogenetic protein signaling pathway can restore the promyelinating niche and have therapeutic effects.
Extrinsic inhibitors at sites of blood-brain barrier disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome the extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodelling at sites of neurovascular dysfunction are largely unknown. By integrating in uiuo two-photon imaging co-registered with electron microscopy and transcriptomics in chronic neuroinflammatory lesions, we found that oligodendrocyte precursor cells clustered perivascularly at sites of limited remyelination with deposition of fibrinogen, a blood coagulation factor abundantly deposited in multiple sclerosis lesions. By developing a screen (OPC-X-screen) to identify compounds that promote remyelination in the presence of extrinsic inhibitors, we showed that known promyelinating drugs did not rescue the extrinsic inhibition of remyelination by fibrinogen. In contrast, bone morphogenetic protein type I receptor blockade rescued the inhibitory fibrinogen effects and restored a promyelinating progenitor niche by promoting myelinating oligodendrocytes, while suppressing astrocyte cell fate, with potent therapeutic effects in chronic models of multiple sclerosis. Thus, abortive oligodendrocyte precursor cell differentiation by fibrinogen is refractory to known promyelinating compounds, suggesting that blockade of the bone morphogenetic protein signalling pathway may enhance remyelinating efficacy by overcoming extrinsic inhibition in neuroinflammatory lesions with vascular damage.
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