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Neuron. 2017 Dec 6;96(5):1003-1012.e7. doi: 10.1016/j.neuron.2017.10.008. Epub 2017 Nov 2.

Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage.

Author information

1
Gladstone Institutes, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA.
2
Gladstone Institutes, San Francisco, CA, USA.
3
Department of Neurology, University of California, San Francisco, CA, USA.
4
Gladstone Institutes, San Francisco, CA, USA; Berkeley City College, Berkeley, CA, USA.
5
Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA; Newborn Brain Research Institute, University of California, San Francisco, CA, USA.
6
National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California, San Diego, La Jolla, CA, USA.
7
Gladstone Institutes, San Francisco, CA, USA; Department of Anesthesia, University of California, San Francisco, CA, USA.
8
Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
9
Faculty of Biology, University of Freiburg, Freiburg, Germany.
10
Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
11
Center for Brain Research, Medical University of Vienna, Vienna, Austria.
12
Department of Pathology, University of California, San Francisco, CA, USA.
13
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
14
Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
15
National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California, San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, California, USA; Salk Institute for Biological Studies, La Jolla, San Diego, California, USA.
16
Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, CA, USA; Department of Paediatrics, University of Cambridge, Cambridge, UK.
17
Gladstone Institutes, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA. Electronic address: kakassoglou@gladstone.ucsf.edu.

Abstract

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

KEYWORDS:

NG2 cells; ancrod; cell fate; fibrin; myelin; neonatal brain injury; neuroinflammation; regeneration; stem/progenitor cells; vasculature

Comment in

PMID:
29103804
PMCID:
PMC5851281
DOI:
10.1016/j.neuron.2017.10.008
[Indexed for MEDLINE]
Free PMC Article

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