Fibrin Inhibits Peripheral Nerve Remyelination by Regulating Schwann Cell Differentiation

Akassoglou, Katerina; Yu, Wei; Akpinar, Pınar; Strickland, Sidney

doi:10.1016/s0896-6273(02)00617-7

Cited by 185 publications

(206 citation statements)

References 74 publications

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“…This corresponds to results in a model of peripheral nerve damage where decreased fibrin deposition was shown to provide a more favourable environment for plasticity and regeneration [7,36], and agrees with more recent data showing that fibrinogen can suppress neurite outgrowth in the CNS [37].…”

Section: Discussionsupporting

confidence: 90%

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

East

Gverić

Baker

et al. 2007

Neuropathology Appl Neurobio

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During neuroinflammation in multiple sclerosis (MS) fibrinogen, not normally present in the brain or spinal cord, enters the central nervous system through a compromised blood-brain barrier. Fibrin deposited on axons is ineffectively removed by tissue plasminogen activator (tPA), a key contributory factor being the upregulation of plasminogen activator inhibitor-1 (PAI-1). Aims: This study investigated the role of PAI-1 during experimental neuroinflammatory disease. Methods: Chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of MS, was induced with spinal cord homogenate in PAI-1 knockout (PAI-1 -/-) and wild type (WT) mice, backcrossed onto the Biozzi background. Results: Disease incidence and clinical severity were reduced in PAI-1 -/-mice, with animals developing clinical signs significantly later than WTs. Clinical relapses were absent in PAI-1 -/-mice and the subsequent reduction in neuroinflammation was coupled with a higher capacity for fibrinolysis in spinal cord samples from PAI-1 -/-mice, in association with increased tPA activity. Axonal damage was less apparent in PAI-1 -/-mice than in WTs, implicating fibrin in both inflammatory and degenerative events during CREAE. Conclusions: PAI-1 is a potential target for therapy in neuroinflammatory degenerative diseases, allowing effective fibrin removal and potentially reducing relapse rate and axonal damage.

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Section: Discussionsupporting

confidence: 90%

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

East

Gverić

Baker

et al. 2007

Neuropathology Appl Neurobio

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“…In this study, we examined adhesion and migration of Schwann cells on FN because this provisional extracellular matrix protein plays a major role in PNS injury and regeneration (26,39). Schwann cells express ␣ v ␤ 8 , which is responsible for adhesion and migration on FN, unlike many other cells that primarily utilize ␣ 5 ␤ 1 and ␣ 4 ␤ 1 (40 -42).…”

Section: Discussionmentioning

confidence: 99%

Low Density Lipoprotein Receptor-related Protein (LRP1) Regulates Rac1 and RhoA Reciprocally to Control Schwann Cell Adhesion and Migration

Mantuano

Gonias

et al. 2010

Journal of Biological Chemistry

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LDL receptor-related protein (LRP1) is expressed by Schwann cells in vivo mainly after injury to the peripheral nervous system (PNS). Schwann cells in primary culture, which provide a model of Schwann cells in the injured PNS, also express abundant LRP1. Herein, we show that LRP1 gene-silencing or treatment with receptor-associated protein (RAP) promotes Schwann cell adhesion and inhibits cell migration on fibronectin. LRP1 genesilencing also resulted in the formation of prominent focal adhesions and actin stress fibers. These changes, which were induced by loss of LRP1 expression or activity, were explained mechanistically by an increase in activated RhoA, coupled with a decrease in activated Rac1. Known LRP1 ligands, including matrix metalloprotease-9, tissue-type plasminogen activator, and In the mature, uninjured peripheral nervous system (PNS), 2 Schwann cells are typically immobile, providing trophic support and in some cases, ensheathing and myelinating axons (1). PNS injury triggers Schwann cell dedifferentiation, allowing these cells to survive, detach from axonal connections, proliferate, and migrate (2). Dedifferentiation is essential for PNS regeneration (3). Many exogenous factors have been reported to stimulate migration of dedifferentiated Schwann cells, including neurotrophin-3 (NT-3), neuregulin-1, and insulinlike growth factor-I (4 -6). These factors promote migration, at least in part, by activating the Rho family GTPases, Rac1 and Cdc42. Rac1 promotes dynamic actin remodeling, lamellipodia formation and random cell migration (7,8). Cdc42 controls cell polarity and allows for directionally persistent cell migration (9). In Schwann cells, the ability of Rac1 to promote cell migration may be counteracted by high levels of activated RhoA and its downstream effector, Rho kinase (10). RhoA activation may be inhibited by Rac1 and Rac1 activation may be inhibited downstream of Rho kinase, allowing for orchestration of these GTPases in the control of cell morphology and migration (11)(12)(13)(14). In development, Schwann cell Rac1 facilitates radial axonal sorting and myelination (15).Gene products that control transformation of the Schwann cell phenotype in PNS injury remain incompletely characterized. We recently identified low density lipoprotein receptorrelated protein (LRP1) as a receptor expressed by Schwann cells mainly after PNS injury (16). LRP1 is a 600-kDa type I transmembrane protein in the LDL receptor gene family, originally characterized as an endocytic receptor, but currently recognized also for its role in cell signaling (17, 18). Diverse proteins implicated in PNS injury, including matrix metalloprotease-9 (MMP-9), tissue-type plasminogen activator (tPA), and activated ␣ 2 -macroglobulin (␣ 2 M) bind to LRP1 and activate Akt and ERK/MAP kinase in Schwann cells in vitro and in the injured . By its effect on cell signaling, LRP1 promotes Schwann cell survival and migration (16,19).Although the increase in Schwann cell migration, observed when cells are treated with MMP-9, has been attr...

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“…In a recent study (Cai et al, 2004), the migration of Schwann cells and organized regeneration of axons through a 14-mm nerve gap in silicone chambers at 10 weeks postoperative was significantly increased in a synergistic manner by the addition of the Schwann cell growth factor heregulin-b1 and poly(L-lactic acid) microfilaments with fewer failures when compared with Matrigel alone, where the matrix density appeared to be inhibitory. If the fibrin matrix persists because of vascular leakage or is not subsequently degraded and cleared, macrophage infiltration may still be present but early remyelination of the new axons by Schwann cells is inhibited (Akassoglou et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Assessment of Axonal Growth into Collagen Nerve Guides Containing VEGF‐Transfected Stem Cells in Matrigel

Kempton

Gonzalez

Leven

et al. 2008

The Anatomical Record

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The early events associated with axonal growth into 10-mm nerve gaps were studied histologically in the rat sciatic nerve model to determine if the outgrowth of blood vessels, Schwann cells, and axons could be enhanced. In the first two experimental groups, collagen nerve guides were filled with either saline or Matrigel. Marrow-derived mesenchymal stem cells (MSCs) were added to Matrigel in two other groups, one of which contained cells transfected with VEGF (MSC/VEGF). After 21 days, the injury site was exposed, fixed, sectioned, and volume fractions of the conduit contents were determined by point counting. The bioresorbable collagen conduits appropriately guided the axons and vessels in a longitudinal direction. The volume fraction of axons was significantly greater in the group with saline when compared with all three groups with Matrigel. This measure had a significant positive correlation with actual counts of myelinated axons. The blood vessel volume fraction in the Matrigel group decreased compared with the saline group, but was restored in the MSC/VEGF group. All Matrigel groups had comparable cellularity and showed a distribution of residual Matrigel in acellular zones. The saline group, by contrast, sustained a network of delicate fibroblastic processes that compartmentalized the nerve and its natural matrix as it became infiltrated by axons as minifascicles. In conclusion, the reduction of axonal outgrowth in the Matrigel groups, when compared with the saline group, suggests that Matrigel may impede the early regenerative process even when enriched by the addition of MSCs or VEGF-transfected cells.

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Fibrin Inhibits Peripheral Nerve Remyelination by Regulating Schwann Cell Differentiation

Cited by 185 publications

References 74 publications

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

Low Density Lipoprotein Receptor-related Protein (LRP1) Regulates Rac1 and RhoA Reciprocally to Control Schwann Cell Adhesion and Migration

Assessment of Axonal Growth into Collagen Nerve Guides Containing VEGF‐Transfected Stem Cells in Matrigel

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