| Literature DB >> 29103804 |
Mark A Petersen1, Jae Kyu Ryu2, Kae-Jiun Chang3, Ainhoa Etxeberria3, Sophia Bardehle2, Andrew S Mendiola2, Wanjiru Kamau-Devers4, Stephen P J Fancy5, Andrea Thor6, Eric A Bushong6, Bernat Baeza-Raja2, Catriona A Syme2, Michael D Wu7, Pamela E Rios Coronado2, Anke Meyer-Franke2, Stephanie Yahn8, Lauriane Pous9, Jae K Lee8, Christian Schachtrup10, Hans Lassmann11, Eric J Huang12, May H Han13, Martina Absinta14, Daniel S Reich14, Mark H Ellisman15, David H Rowitch16, Jonah R Chan3, Katerina Akassoglou17.
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.Entities:
Keywords: NG2 cells; ancrod; cell fate; fibrin; myelin; neonatal brain injury; neuroinflammation; regeneration; stem/progenitor cells; vasculature
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Year: 2017 PMID： 29103804 PMCID： PMC5851281 DOI： 10.1016/j.neuron.2017.10.008
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173