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

Mark A. Petersen; Jae Kyu Ryu; Kae Jiun Chang; Ainhoa Etxeberria; Sophia Bardehle; Andrew S. Mendiola; Wanjiru Kamau-Devers; Stephen P.J. Fancy; Andrea Thor; Eric A. Bushong; Bernat Baeza-Raja; Catriona A. Syme; Michael D. Wu; Pamela E. Rios Coronado; Anke Meyer-Franke; Stephanie Yahn; Lauriane Pous; Jae K. Lee; Christian Schachtrup; Hans Lassmann; Eric J. Huang; May H. Han; Martina Absinta; Daniel S. Reich; Mark H. Ellisman; David H. Rowitch; Jonah R. Chan; Katerina Akassoglou

doi:10.1016/j.neuron.2017.10.008

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

Mark A. Petersen, Jae Kyu Ryu, Kae Jiun Chang, Ainhoa Etxeberria, Sophia Bardehle, Andrew S. Mendiola, Wanjiru Kamau-Devers, Stephen P.J. Fancy, Andrea Thor, Eric A. Bushong, Bernat Baeza-Raja, Catriona A. Syme, Michael D. Wu, Pamela E. Rios Coronado, Anke Meyer-Franke, Stephanie Yahn, Lauriane Pous, Jae K. Lee, Christian Schachtrup, Hans LassmannEric J. Huang, May H. Han, Martina Absinta, Daniel S. Reich, Mark H. Ellisman, David H. Rowitch, Jonah R. Chan, Katerina Akassoglou

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1003-1012.e7
Journal	Neuron
Volume	96
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2017.10.008
State	Published - Dec 6 2017
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2017.10.008

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Petersen, M. A., Ryu, J. K., Chang, K. J., Etxeberria, A., Bardehle, S., Mendiola, A. S., Kamau-Devers, W., Fancy, S. P. J., Thor, A., Bushong, E. A., Baeza-Raja, B., Syme, C. A., Wu, M. D., Rios Coronado, P. E., Meyer-Franke, A., Yahn, S., Pous, L., Lee, J. K., Schachtrup, C., ... Akassoglou, K. (2017). Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage. Neuron, 96(5), 1003-1012.e7. https://doi.org/10.1016/j.neuron.2017.10.008

Petersen, MA, Ryu, JK, Chang, KJ, Etxeberria, A, Bardehle, S, Mendiola, AS, Kamau-Devers, W, Fancy, SPJ, Thor, A, Bushong, EA, Baeza-Raja, B, Syme, CA, Wu, MD, Rios Coronado, PE, Meyer-Franke, A, Yahn, S, Pous, L, Lee, JK, Schachtrup, C, Lassmann, H, Huang, EJ, Han, MH, Absinta, M, Reich, DS, Ellisman, MH, Rowitch, DH, Chan, JR & Akassoglou, K 2017, 'Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage', Neuron, vol. 96, no. 5, pp. 1003-1012.e7. https://doi.org/10.1016/j.neuron.2017.10.008

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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",

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doi = "10.1016/j.neuron.2017.10.008",

language = "English (US)",

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T1 - Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage

AU - Petersen, Mark A.

AU - Ryu, Jae Kyu

AU - Chang, Kae Jiun

AU - Etxeberria, Ainhoa

AU - Bardehle, Sophia

AU - Mendiola, Andrew S.

AU - Kamau-Devers, Wanjiru

AU - Fancy, Stephen P.J.

AU - Thor, Andrea

AU - Bushong, Eric A.

AU - Baeza-Raja, Bernat

AU - Syme, Catriona A.

AU - Wu, Michael D.

AU - Rios Coronado, Pamela E.

AU - Meyer-Franke, Anke

AU - Yahn, Stephanie

AU - Pous, Lauriane

AU - Lee, Jae K.

AU - Schachtrup, Christian

AU - Lassmann, Hans

AU - Huang, Eric J.

AU - Han, May H.

AU - Absinta, Martina

AU - Reich, Daniel S.

AU - Ellisman, Mark H.

AU - Rowitch, David H.

AU - Chan, Jonah R.

AU - Akassoglou, Katerina

PY - 2017/12/6

Y1 - 2017/12/6

N2 - 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.

AB - 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.

KW - NG2 cells

KW - ancrod

KW - cell fate

KW - fibrin

KW - myelin

KW - neonatal brain injury

KW - neuroinflammation

KW - regeneration

KW - stem/progenitor cells

KW - vasculature

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U2 - 10.1016/j.neuron.2017.10.008

DO - 10.1016/j.neuron.2017.10.008

M3 - Article

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AN - SCOPUS:85035018116

SN - 0896-6273

VL - 96

SP - 1003-1012.e7

JO - Neuron

JF - Neuron

IS - 5

ER -

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

Abstract

Keywords

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