Hepatocyte growth factor reduces astrocytic scar formation and promotes axonal growth beyond glial scars after spinal cord injury

Jeong, Soo Ryeong; Kwon, Min Jung; Lee, Hwan Goo; Joe, Eun Hye; Lee, Jae Ho; Kim, Sung Soo; Suh‐Kim, Haeyoung; Kim, Byung Gon

doi:10.1016/j.expneurol.2011.10.021

Cited by 91 publications

(68 citation statements)

References 56 publications

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“…Previous research focuses largely on improving neurological manifestations through the improvement of sensory function and locomotor function [1][2][3][4], but study of the bloodLi-Bing Ye and Xi-Chong Yu contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

Xia

et al. 2016

Neurotherapeutics

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The blood-spinal cord barrier (BSCB) plays important roles in the recovery of spinal cord injury (SCI), and caveolin-1 is essential for the integrity and permeability of barriers. Basic fibroblast growth factor (bFGF) is an important neuroprotective protein and contributes to the survival of neuronal cells. This study was designed to investigate whether bFGF is beneficial for the maintenance of junction proteins and the integrity of the BSCB to identify the relations with caveolin-1 regulation. We examined the integrity of the BSCB with Evans blue dye and fluorescein isothiocyanate-dextran extravasation, measured the junction proteins and matrix metalloproteinases, and evaluated the locomotor function recovery. Our data indicated that bFGF treatment improved the recovery of BSCB and functional locomotion in contusive SCI model rats, reduced the expression and activation of matrix metalloproteinase-9, and increased the expressions of caveolin-1 and junction proteins, including occludin, claudin-5, p120-catenin, and β-catenin. In the brain, in microvascular endothelial cells, bFGF treatment increased the levels of junction proteins, caveolin-1 small interfering RNA abolished the protective effect of bFGF under oxygen-glucose deprivation conditions, and the expression of fibroblast growth factor receptor 1 and co-localization with caveolin-1 decreased significantly, which could not be reversed by bFGF treatment. These findings provide a novel mechanism underlying the beneficial effects of bFGF on the BSCB and recovery of SCI, especially the regulation of caveolin-1.

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Section: Introductionmentioning

confidence: 99%

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

Xia

et al. 2016

Neurotherapeutics

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“…miR-145 likely exhibits global control over astrogliosis, in contrast to miR-21, which specifically controls the hypertrophic stage of astrogliosis. Finally, ex vivo gene therapy with HGF reduces transforming growth factor beta (TGF-β) levels, limits astrocytic scar formation and promotes axonal regeneration beyond the glial scar after SCI [Jeong et al, 2012]. …”

Section: Gene Therapymentioning

confidence: 99%

Tissue Engineering Approaches to Modulate the Inflammatory Milieu following Spinal Cord Injury

Dumont¹,

Margul

Shea

2016

Cells Tissues Organs

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Tissue engineering strategies have shown promise in promoting healing and regeneration after spinal cord injury (SCI); however, these strategies are limited by inflammation and the immune response. Infiltration of cells of the innate and adaptive immune responses and the inflammation that follows cause secondary damage adjacent to the injury, increased scarring, and a potently inhibitory environment for the regeneration of damaged neurons. While the inflammation that ensues is typically associated with limited regeneration, the immune response is a crucial element in the closing of the blood-brain barrier, minimizing the spread of injury, and initiating healing. This review summarizes the strategies that have been developed to modulate the immune response towards an anti-inflammatory environment that is permissive to the regeneration of neurons, glia, and parenchyma. We focus on the use of biomaterials, biologically active molecules, gene therapy, nanoparticles, and stem cells to modulate the immune response, and illustrate concepts for future therapies. Current clinical treatments for SCI are limited to systemic hypothermia or methylprednisolone, which both act by systemically mitigating the effects of immune response but have marginal efficacy. Herein, we discuss emerging research strategies to further enhance these clinical treatments by directly targeting specific aspects of the immune response.

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“…The up-regulation of HGF, a potent growth factor with pleiotropic activity related to tissue protection and regeneration that is enhanced in reactive astrocytes in vivo, is particularly relevant (Shimamura et al, 2007;Nakamura et al, 2011;Jeong et al, 2012). Since astrocytes exert beneficial effects by regulating local immune responses, the increased expression of this molecule by these cells when Fxn is lacking suggests that a physiological compensatory mechanism may be triggered to protect them.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

Loría

Díaz‐Nido

2015

Neurobiology of Disease

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Friedreich's ataxia (FA) is a recessive, predominantly neurodegenerative disorder caused in most cases by mutations in the first intron of the frataxin (FXN) gene. This mutation drives the expansion of a homozygous GAA repeat that results in decreased levels of FXN transcription and frataxin protein. Frataxin (Fxn) is a ubiquitous mitochondrial protein involved in iron-sulfur cluster biogenesis, and a decrease in the levels of this protein is responsible for the symptoms observed in the disease. Although the pathological manifestations of FA are mainly observed in neurons of both the central and peripheral nervous system, it is not clear if changes in non-neuronal cells may also contribute to the pathogenesis of FA, as recently suggested for other neurodegenerative disorders. Therefore, the aims of this study were to generate and characterize a cell model of Fxn deficiency in human astrocytes (HAs) and to evaluate the possible involvement of non-cell autonomous processes in FA. To knockdown frataxin in vitro, we transduced HAs with a specific shRNA lentivirus (shRNA37), which produced a decrease in both frataxin mRNA and protein expression, along with mitochondrial superoxide production, and signs of p53-mediated cell cycle arrest and apoptotic cell death. To test for non-cell autonomous interactions we cultured wild-type mouse neurons in the presence of frataxin-deficient astrocyte conditioned medium, which provoked a delay in the maturation of these neurons, a decrease in neurite length and enhanced cell death. Our findings confirm a detrimental effect of frataxin silencing, not only for astrocytes, but also for neuron-glia interactions, underlining the need to take into account the role of non-cell autonomous processes in FA.

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Hepatocyte growth factor reduces astrocytic scar formation and promotes axonal growth beyond glial scars after spinal cord injury

Cited by 91 publications

References 56 publications

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

Tissue Engineering Approaches to Modulate the Inflammatory Milieu following Spinal Cord Injury

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

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