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Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage.

ABSTRACT: Scar formation in the nervous system begins within hours after traumatic injury and is characterized primarily by reactive astrocytes depositing proteoglycans that inhibit regeneration. A fundamental question in CNS repair has been the identity of the initial molecular mediator that triggers glial scar formation. Here we show that the blood protein fibrinogen, which leaks into the CNS immediately after blood-brain barrier (BBB) disruption or vascular damage, serves as an early signal for the induction of glial scar formation via the TGF-beta/Smad signaling pathway. Our studies revealed that fibrinogen is a carrier of latent TGF-beta and induces phosphorylation of Smad2 in astrocytes that leads to inhibition of neurite outgrowth. Consistent with these findings, genetic or pharmacologic depletion of fibrinogen in mice reduces active TGF-beta, Smad2 phosphorylation, glial cell activation, and neurocan deposition after cortical injury. Furthermore, stereotactic injection of fibrinogen into the mouse cortex is sufficient to induce astrogliosis. Inhibition of the TGF-beta receptor pathway abolishes the fibrinogen-induced effects on glial scar formation in vivo and in vitro. These results identify fibrinogen as a primary astrocyte activation signal, provide evidence that deposition of inhibitory proteoglycans is induced by a blood protein that leaks in the CNS after vasculature rupture, and point to TGF-beta as a molecular link between vascular permeability and scar formation.

SUBMITTER: Schachtrup C

PROVIDER: S-EPMC2871011 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage.

Schachtrup Christian C Ryu Jae K JK Helmrick Matthew J MJ Vagena Eirini E Galanakis Dennis K DK Degen Jay L JL Margolis Richard U RU Akassoglou Katerina K

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100401 17

Scar formation in the nervous system begins within hours after traumatic injury and is characterized primarily by reactive astrocytes depositing proteoglycans that inhibit regeneration. A fundamental question in CNS repair has been the identity of the initial molecular mediator that triggers glial scar formation. Here we show that the blood protein fibrinogen, which leaks into the CNS immediately after blood-brain barrier (BBB) disruption or vascular damage, serves as an early signal for the ind ...[more]

PMID: 20427645

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Project description:Vascular calcification is an actively regulated process that culminates in organized extracellular matrix mineral deposition by osteoblast-like cells. The origins of the osteoblastic cells involved in this process and the underlying mechanisms remain to be defined. We previously revealed that active transforming growth factor (TGF?) released from the injured arteries mobilizes mesenchymal stem cells (MSCs) to the blood stream and recruits the cells to the injured vessels for neointima formation. In this study, we used a low-density lipoprotein receptor (LDLR)-deficient mouse model (ldlr(-/-)), which develop progressive arterial calcification after having fed high-fat western diets (HFD), to examine whether TGF? is involved in the mobilization of MSCs during vascular calcification. Nestin(+)/Sca1(+) cells were recruited to the diseased aorta at earlier time points, and osteocalcin(+) osteoblasts and the aortic calcification were seen at later time point in these mice. Importantly, we generated parabiotic pairs with shared blood circulation by crossing ldlr(-/-)mice fed HFD with transgenic mice, in which all the MSC-derived cells were fluorescently labeled. The labeled cells were detected not only in the peripheral blood but also in the arterial lesions in ldlr(-/-) mouse partners, and these blood circulation-originated cells gave rise to Ocn(+) osteoblastic cells at the arterial lesions. Both active TGF?1 levels and MSCs in circulating blood were upregulated at the same time points when these cells appeared at the aortic tissue. Further, conditioned medium prepared by incubating the aortae from ldlr(-/-)mice fed HFD stimulated the migration of MSCs in the ex vivo transwell assays, and either TGF? neutralizing antibody or the inhibitor of TGF? Receptor I kinase (T?RI) antagonized this effect. Importantly, treatment of the mice with T?RI inhibitor blocked elevated blood MSC numbers and their recruitment to the arterial lesions. These findings suggest that TGF?-recruited MSCs to the diseased vasculature contribute to the development of osteogenic vascular calcification.

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Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage.

Publications

Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage.

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