Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo

Tönges, Lars; Ostendorf, Thomas; Lamballe, Fabienne; Genestine, Matthieu; Dono, Rosanna; Koch, Jan Christoph; Bähr, Mathias; Maina, Flavio; Lingor, Paul

doi:10.1111/j.1471-4159.2011.07257.x

Cited by 61 publications

(37 citation statements)

References 41 publications

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“…PI3K-dependent Akt phosphorylation and subsequent increased synthesis of anti-apoptotic bcl proteins represents a common mechanism of regulating RGC survival shared by many growth factors such as BDNF, IGF, CNTF, HGF [23], [70]–[73], and cytokines such as IL-1β and erythropoietin [74], [75]. Recent studies have shown that the Akt isoforms, 1, 2, and 3 are present in the RGC layer in the rat retina, and all three subtypes are able to block RGC apoptosis after RIRI [76].…”

Section: Discussionmentioning

confidence: 99%

β1 Integrin-Focal Adhesion Kinase (FAK) Signaling Modulates Retinal Ganglion Cell (RGC) Survival

et al. 2012

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Extracellular matrix (ECM) integrity in the central nervous system (CNS) is essential for neuronal homeostasis. Signals from the ECM are transmitted to neurons through integrins, a family of cell surface receptors that mediate cell attachment to ECM. We have previously established a causal link between the activation of the matrix metalloproteinase-9 (MMP-9), degradation of laminin in the ECM of retinal ganglion cells (RGCs), and RGC death in a mouse model of retinal ischemia-reperfusion injury (RIRI). Here we investigated the role of laminin-integrin signaling in RGC survival in vitro, and after ischemia in vivo. In purified primary rat RGCs, stimulation of the β1 integrin receptor with laminin, or agonist antibodies enhanced RGC survival in correlation with activation of β1 integrin’s major downstream regulator, focal adhesion kinase (FAK). Furthermore, β1 integrin binding and FAK activation were required for RGCs’ survival response to laminin. Finally, in vivo after RIRI, we observed an up-regulation of MMP-9, proteolytic degradation of laminin, decreased RGC expression of β1 integrin, FAK and Akt dephosphorylation, and reduced expression of the pro-survival molecule bcl-xL in the period preceding RGC apoptosis. RGC death was prevented, in the context of laminin degradation, by maintaining β1 integrin activation with agonist antibodies. Thus, disruption of homeostatic RGC-laminin interaction and signaling leads to cell death after retinal ischemia, and maintaining integrin activation may be a therapeutic approach to neuroprotection.

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Section: Discussionmentioning

confidence: 99%

β1 Integrin-Focal Adhesion Kinase (FAK) Signaling Modulates Retinal Ganglion Cell (RGC) Survival

et al. 2012

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“…These changes should result from the activity of retinal neuronal cells and, not by only astrocytes considering the abundance of astrocytes in the retina. It has been reported that c-met , a HGF receptor gene, was present in RGCs and exogenous HGF protected RGCs through HGF receptor signaling 24, 25 . Therefore, progranulin may contribute to the direct protection of RGCs through HGF receptor signaling at immature stage followed by the activation of astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Progranulin deficiency causes the retinal ganglion cell loss during development

Kuse

Tsuruma

Mizoguchi

et al. 2017

Sci Rep

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Astrocytes are glial cells that support and protect neurons in the central nervous systems including the retina. Retinal ganglion cells (RGCs) are in contact with the astrocytes and our earlier findings showed the reduction of the number of cells in the ganglion cell layer in adult progranulin deficient mice. In the present study, we focused on the time of activation of the astrocytes and the alterations in the number of RGCs in the retina and optic nerve in progranulin deficient mice. Our findings showed that the number of Brn3a-positive cells was reduced and the expression of glial fibrillary acidic protein (GFAP) was increased in progranulin deficient mice. The progranulin deficient mice had a high expression of GFAP on postnatal day 9 (P9) but not on postnatal day 1. These mice also had a decrease in the number of the Brn3a-positive cells on P9. Taken together, these findings indicate that the absence of progranulin can affect the survival of RGCs subsequent the activation of astrocytes during retinal development.

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“…Thus, the mixture of type-1 collagen and b-TCP was expected to provide a biodegradable scaffold for local delivery of HGF. On the other hand, previous studies using local administration of HGF in various models in different species including rabbit revealed significant therapeutic effects of 100 lg HGF [11,[31][32][33][34]. Therefore, we selected a dose of 100 lg HGF/injection for the HGF/b-TCP/collagen complex because HGF was expected to exert biological effects and we could evaluate if HGF would have therapeutic benefits in this rabbit model.…”

Section: Discussionmentioning

confidence: 99%

Repair of segmental bone defects in rabbit tibia promoted by a complex of β-tricalcium phosphate and hepatocyte growth factor

Goshima

Nakase

et al. 2012

Journal of Orthopaedic Science

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Background Segmental bone defect repair remains a clinical and scientific challenge with increasing interest focused on bone tissue engineering. Clinical studies are ongoing to address application of hepatocyte growth factor (HGF) for treatment of some diseases; however, the use of HGF in bone tissue engineering has not been addressed. This study was performed to evaluate the effect of HGF in a complex of b-tricalcium phosphate (b-TCP) and collagen in repairing segmental bone defects. Methods Segmental bone defects 5 mm long were created in the middle of the tibial shafts of rabbits. The defect was stabilized with external fixators and implanted with a complex of b-TCP granules and collagen, with or without 100 lg recombinant human HGF. Biweekly, bone regeneration and b-TCP resorption were assessed radiographically and histologically. At 4 and 8 weeks, bone regeneration was evaluated by use of micro-computed tomography and mechanical tests. Results Compared with the bone tissue treated with b-TCP and collagen, mineralization, angiogenesis, new bone formation, and absorption of b-TCP were promoted 4 weeks postoperatively by treatment with HGF in the b-TCP and collagen group. These changes were associated with promoting biomechanical regeneration. By 8 weeks, the formation of bone marrow in newly generated bone and absorption of the b-TCP granules were completed in a shorter period by combining HGF with b-TCP and collagen, compared with tissues without HGF. Conclusions The combined application of HGF in a b-TCP and collagen matrix promoted histological bone healing and augmented mechanical strength of the healing bone, particularly in the early stages. The combined use of HGF and b-TCP for treatment of bone defects made a substantial difference.

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Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo

Cited by 61 publications

References 41 publications

β1 Integrin-Focal Adhesion Kinase (FAK) Signaling Modulates Retinal Ganglion Cell (RGC) Survival

β1 Integrin-Focal Adhesion Kinase (FAK) Signaling Modulates Retinal Ganglion Cell (RGC) Survival

Progranulin deficiency causes the retinal ganglion cell loss during development

Repair of segmental bone defects in rabbit tibia promoted by a complex of β-tricalcium phosphate and hepatocyte growth factor

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