@article{8f645318c1c3474d91c6fa2834bb1096,
title = "Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage",
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. Extrinsic inhibitors contribute to remyelination failure in neurological diseases. Petersen et al. identify the blood coagulation factor fibrinogen as an activator of BMP receptor signaling in oligodendrocyte progenitor cells that may be targeted therapeutically to promote remyelination.",
keywords = "NG2 cells, ancrod, cell fate, fibrin, myelin, neonatal brain injury, neuroinflammation, regeneration, stem/progenitor cells, vasculature",
author = "Petersen, {Mark A.} and Ryu, {Jae Kyu} and Chang, {Kae Jiun} and Ainhoa Etxeberria and Sophia Bardehle and Mendiola, {Andrew S.} and Wanjiru Kamau-Devers and Fancy, {Stephen P.J.} and Andrea Thor and Bushong, {Eric A.} and Bernat Baeza-Raja and Syme, {Catriona A.} and Wu, {Michael D.} and {Rios Coronado}, {Pamela E.} and Anke Meyer-Franke and Stephanie Yahn and Lauriane Pous and Lee, {Jae K.} and Christian Schachtrup and Hans Lassmann and Huang, {Eric J.} and Han, {May H.} and Martina Absinta and Reich, {Daniel S.} and Ellisman, {Mark H.} and Rowitch, {David H.} and Chan, {Jonah R.} and Katerina Akassoglou",
note = "Funding Information: We thank Reshmi Tognatta for discussions; Belinda Cabriga, Yun-An Shen, Marielle Cavrois, and Nandhini Raman for expert technical assistance; John Lewis for graphics; and Gary Howard for editorial. The Gladstone FACS core was supported by NIH P30 AI027763 , NIH S10 RR028962 , Department of Defense (DoD) W81XWH-11-1-0562 , and the Gladstone Institutes from a National Center for Research Resources Grant RR18928 . This work was supported by NIH/NICHD K12-HD072222 grant and Pediatric Scientist Development Program fellowship ( March of Dimes 4-FY10-461 and NIH/NICHD K12-HD000850 ) to M.A.P.; A Race to Erase MS Young Investigator Award and American Heart Association Scientist Development Grant 16SDG30170014 to J.K.R.; National Multiple Sclerosis Society (NMSS) fellowship grants FG-2093-A-1 to M.A. and FG-1507-05195 to K.J.C.; the Marilyn Hilton Bridging Award for Physician-Scientists to M.A., the NINDS Intramural Research Program to D.S.R.; NIH R01 NS027177 , R01 GM086197 , and P41 GM103412 to M.H.E. for support of the National Center for Microscopy and Imaging Research; the NMSS RG5203 , NIH/NINDS R01 NS062796 , and the Rachleff Endowment to J.R.C.; and the NIH/NINDS R35 NS097976 , NMSS RG4985 , DoD MS160082 , and Conrad N. Hilton Foundation grants to K.A. K.A. is a co-founder of MedaRed, Inc., and K.A., J.K.R., and A.M.F. are named inventors on patents and patent applications related to fibrin. Their interests are managed by the Gladstone Institutes in accordance with its conflict of interest policy. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = dec,
day = "6",
doi = "10.1016/j.neuron.2017.10.008",
language = "English (US)",
volume = "96",
pages = "1003--1012.e7",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}