Ephrin-B2 and EphB2 Regulation of Astrocyte-Meningeal Fibroblast Interactions in Response to Spinal Cord Lesions in Adult Rats

Bundesen, Liza Q.; Scheel, T.; Bregman, Barbara S.; Kromer, Lawrence F.

doi:10.1523/jneurosci.23-21-07789.2003

Cited by 296 publications

(287 citation statements)

References 72 publications

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“…Members of this family are up-regulated following CNS injury (18,19). EphA4 has been implicated in the response to injury both as an astrocyte and as a neuronally expressed protein, but its functional role in recovery from neuronal injury is not clear (20)(21)(22)(23). Macrophage EphB3 has also been implicated in adult axon regeneration (24).…”

Section: Neurology | Locomotionmentioning

confidence: 99%

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Duffy

Wang

Siegel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Recovery of neurological function after traumatic injury of the adult mammalian central nervous system is limited by lack of axonal growth. Myelin-derived inhibitors contribute to axonal growth restriction, with ephrinB3 being a developmentally important axonal guidance cue whose expression in mature oligodendrocytes suggests a role in regeneration. Here we explored the in vivo regeneration role of ephrinB3 using mice lacking a functional ephrinB3 gene. We confirm that ephrinB3 accounts for a substantial portion of detergent-resistant myelin-derived inhibition in vitro. To assess in vivo regeneration, we crushed the optic nerve and examined retinal ganglion fibers extending past the crush site. Significantly increased axonal regeneration is detected in ephrinB3 −/− mice. Studies of spinal cord injury in ephrinB3 −/− mice must take into account altered spinal cord development and an abnormal hopping gait before injury. In a near-total thoracic transection model, ephrinB3 −/− mice show greater spasticity than wild-type mice for 2 mo, with slightly greater hindlimb function at later time points, but no evidence for axonal regeneration. After a dorsal hemisection injury, increased corticospinal and raphespinal growth in the caudal spinal cord are detected by 6 wk. This increased axonal growth is accompanied by improved locomotor performance measured in the open field and by kinematic analysis. Thus, ephrinB3 contributes to myelin-derived axonal growth inhibition and limits recovery from adult CNS trauma.

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Section: Neurology | Locomotionmentioning

confidence: 99%

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Duffy

Wang

Siegel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This result does not exclude possible roles for other ephrins and their Eph receptors in inhibition of regeneration after injury. For example, Bundesen et al (27) observed that ephrin-B2 is up-regulated in astrocytes and regulates astrocyte-meningeal fibroblast interactions after SCI in mice. Additionally, EphA (28) and EphB3 (29,30) receptors are up-regulated in cells surrounding injury sites in rats, suggesting that these molecules may also contribute to the nonpermissive environment in chronic SCI.…”

Section: Resultsmentioning

confidence: 99%

Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

Benson

Romero

Lush

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

276

191

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The inability of CNS axons to regenerate after traumatic spinal cord injury is due, in part, to the inhibitory effects of myelin. The three major previously identified constituents of this activity (Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein) were isolated based on their potent inhibition of axon outgrowth in vitro. All three myelin components transduce their inhibitory signals through the same Nogo receptor͞p75 neurotrophin receptor͞LINGO-1 (NgR1͞p75͞LINGO-1) complex. In this study, we considered that molecules known to act as repellants in vertebrate embryonic axonal pathfinding may also inhibit regeneration. In mice, ephrin-B3 functions during development as a midline repellant for axons of the corticospinal tract. We therefore investigated whether this repellant was expressed in the adult spinal cord and retained inhibitory activity. We demonstrate that ephrin-B3 is expressed in postnatal myelinating oligodendrocytes and, by using primary CNS neurons, show that ephrin-B3 accounts for an inhibitory activity equivalent to that of the other three myelin-based inhibitors, acting through p75, combined. Our data describe a known vertebrate axon guidance molecule as a myelinbased inhibitor of neurite outgrowth.spinal cord injury ͉ regeneration ͉ axon ͉ Eph receptor T he corticospinal tract (CST) is the major spinal axon bundle responsible for fine locomotor control. Damage to this tract contributes to the permanent loss of motor control that is the most visible hallmark of spinal cord injury (SCI). These, and other axons of the CNS damaged in SCI, do not regenerate, in part, because of the nonpermissive environment of myelin in the mature CNS (1). Constituents of this repressive activity in myelin include Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) (reviewed in ref.2). The recently identified Nogo receptor (NgR1) is a glycosylphosphatidylinositol-linked molecule that binds the 66-aa extracellular loop of Nogo (Nogo-66) and transduces its inhibitory activity when expressed in neurons (3). Surprisingly, MAG and OMgp also bind the NgR1 (4-6) in a complex with the p75 neurotrophin receptor and the newly characterized leucine rich repeat transmembrane protein LINGO-1. p75 and LINGO-1 are requisite signaling components for inhibition by Nogo-66, MAG, and OMgp as p75 Ϫ/Ϫ cerebellar granule neurons (CGNs) or dorsal root ganglion (DRG) neurons exhibit reduced sensitivity to these three inhibitors and to inhibition by CNS myelin (7), and NgR1͞p75 complexes confer sensitivity to these inhibitors only in the presence of LINGO-1 (8).Although it is thought that Nogo, MAG, and OMgp may act in the uninjured CNS to control aberrant sprouting and stabilize mature connections (9), their normal and developmental roles remain a mystery. Axon repellants such as semaphorins, slits, and ephrins play critical roles in tract formation during embryonic development (10). We previously proposed that such molecules may function as inhibitors of regeneration in the...

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“…28 While astroglia can provide a favorable environment for regeneration, 29 fibroblastlike cells are known to segregate astrocytes from the lesion via ephrin-B2/EphB2 signaling. 30 Conditional deletion of PDGFRb during stroke resulted in larger infarcts and disruption of astroglial scar formation, 31 suggesting a potential crosstalk between PDGFRb þ cells and astroglia. Inflammatory cells such as macrophages, neutrophils, and lymphocytes modulate fibrosis via the release of interleukins and growth factors, including PDGF and transforming growth factor-b.…”

Section: Discussionmentioning

confidence: 99%

Early Loss of Pericytes and Perivascular Stromal Cell-Induced Scar Formation after Stroke

Fernández-Klett

Potas

Hilpert

et al. 2012

J Cereb Blood Flow Metab

205

249

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Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRb) þ and CD105 þ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRb þ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.

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Ephrin-B2 and EphB2 Regulation of Astrocyte-Meningeal Fibroblast Interactions in Response to Spinal Cord Lesions in Adult Rats

Cited by 296 publications

References 72 publications

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

Early Loss of Pericytes and Perivascular Stromal Cell-Induced Scar Formation after Stroke

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