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

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          Abstract

          <p id="P1">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 homologue 1 (DMH1) or CRISPR/Cas9 activin A receptor type I <i>(ACVR1)</i> 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. </p><p id="P2">Extrinsic inhibitors contribute to remyelination failure in neurological diseases. Petersen <i>et al</i>. identify the blood coagulation factor fibrinogen as an activator of BMP receptor signaling in oligodendrocyte progenitor cells that can be targeted therapeutically to promote remyelination. </p>

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          Author and article information

          Journal
          Neuron
          Neuron
          Elsevier BV
          08966273
          December 2017
          December 2017
          : 96
          : 5
          : 1003-1012.e7
          Article
          10.1016/j.neuron.2017.10.008
          5851281
          29103804
          13071ed8-2626-4b06-af53-d561292b12de
          © 2017

          http://www.elsevier.com/tdm/userlicense/1.0/

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