Vascular Endothelial Growth Factor Receptor 1 Morpholino Decreases Angiogenesis in a Murine Corneal Suture Model

Cho, Yang Kyung; Uehara, Hironori; Young, Jason R.; Archer, Bonnie; Zhang, Xiaohui; Ambati, Balamurali K.

doi:10.1167/iovs.11-8391

Cited by 13 publications

(13 citation statements)

References 30 publications

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“…Furthermore, limbal LV were previously reported to be sustained by corneal macrophages in C57Bl/6 mice 26 . To analyze whether the steady state maintenance of the limbal blood and lymphatic vasculature in Balb/c mice, which are frequently used in corneal neovascularization models 16,27–29 , also depends on the presence of macrophages, we investigated the impact of macrophage depletion on the resting corneal vasculature in this mouse strain (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis

Kiesewetter

Cursiefen

Eming

et al. 2019

Sci Rep

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Macrophages are critical mediators of injury-associated corneal hemangiogenesis (HA) and lymphangiogenesis (LA). Yet, molecular regulators of the hem- and lymphangiogenic potential of corneal wound macrophages are poorly understood. Using two different mouse models of acute (perforating corneal incision injury) and chronic (corneal suture placement model) corneal injury, here we identified distinct functions of early- versus late-phase corneal wound macrophages in corneal HA and LA. Whereas early-phase wound macrophages are essential for initiation and progression of injury-mediated corneal HA and LA, late-phase wound macrophages control maintenance of established corneal lymphatic vessels, but not blood vessels. Furthermore, our findings reveal that the hem- and lymphangiogenic potential of corneal wound macrophages is controlled by the type of the corneal damage. Whereas perforating corneal incision injury induced primarily wound macrophages with lymphangiogenic potential, corneal suture placement provoked wound macrophages with both hem- and lymphangiogenic potential. Our findings highlight a previously unrecognized injury-context dependent role of early- versus late-phase corneal wound macrophages with potential clinical impact on therapy development for sight-threatening corneal neovascular diseases.

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Section: Resultsmentioning

confidence: 99%

Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis

Kiesewetter

Cursiefen

Eming

et al. 2019

Sci Rep

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“…It is well accepted that sFLT-1 is an important factor in corneal avascularity. 58 – 61 It is produced mainly by corneal epithelial cells. 11 In our in vivo studies, the contribution of epithelial secreted sFLT-1 was not specifically studied; however, our in vitro results confirm that Co-MSCs secrete sFLT-1 at high enough level to inhibit angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1

Eslani

Putra

Shen

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeTo evaluate the angiogenic properties of corneal derived mesenchymal stromal cells (Co-MSC).MethodsCo-MSCs were extracted from human cadaver, and wild-type (C57BL/6J) and SERPINF1−/− mice corneas. The MSC secretome was collected in a serum-free medium. Human umbilical vein endothelial cell (HUVEC) tube formation and fibrin gel bead assay (FIBA) sprout formation were used to assess the angiogenic properties of Co-MSC secretome. Complete corneal epithelial debridement was used to induce corneal neovascularization in wild-type mice. Co-MSCs embedded in fibrin gel was applied over the debrided cornea to evaluate the angiogenic effects of Co-MSCs in vivo. Immunoprecipitation was used to remove soluble fms-like tyrosine kinase-1 (sFLT-1) and pigment epithelium-derived factor (PEDF, SERPINF1 gene) from the Co-MSC secretome.ResultsCo-MSC secretome significantly inhibited HUVECs tube and sprout formation. Co-MSCs from different donors consistently contained high levels of antiangiogenic factors including sFLT-1 and PEDF; and low levels of the angiogenic factor VEGF-A. In vivo, application of Co-MSCs to mouse corneas after injury prevented the development of corneal neovascularization. Removing PEDF or sFLT-1 from the secretome significantly diminished the antiangiogenic effects of Co-MSCs. Co-MSCs isolated from SERPINF1−/− mice had significantly reduced antiangiogenic effects compared to SERPINF1+/+ (wild-type) Co-MSCs.ConclusionsThese results illustrate the direct antiangiogenic properties of Co-MSCs, the importance of sFLT-1 and PEDF, and their potential clinical application for preventing pathologic corneal neovascularization.

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“…184 Recently, morpholine oligonucleotides have been designed to induce a molecular “anti-angiogenic” switch whereby it generates sFlt-1 through alternative splicing of Flt-1 pre-mRNA, leading to inhibition of corneal neovascularization, decreased corneal lymphangiogenesis, and increased corneal allograft survival. 161,185–187 …”

Section: Discussionmentioning

confidence: 99%

Gene Therapy in Corneal Transplantation

Qazi

Hamrah

2013

Seminars in Ophthalmology

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Corneal transplantation is the most commonly performed organ transplantation. Immune privilege of the cornea is widely recognized, partly because of the relatively favorable outcome of corneal grafts. The first-time recipient of corneal allografts in an avascular, low-risk setting can expect a 90% success rate without systemic immunosuppressive agents and histocompatibility matching. However, immunologic rejection remains the major cause of graft failure, particularly in patients with a high risk for rejection. Corticosteroids remain the first-line therapy for the prevention and treatment of immune rejection. However, current pharmacological measures are limited in their side-effect profiles, repeated application, lack of targeted response, and short duration of action. Experimental ocular gene therapy may thus present new horizons in immunomodulation. From efficient viral vectors to sustainable alternative splicing, we discuss the progress of gene therapy in promoting graft survival and postulate further avenues for gene-mediated prevention of allogeneic graft rejection.

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Vascular Endothelial Growth Factor Receptor 1 Morpholino Decreases Angiogenesis in a Murine Corneal Suture Model

Abstract: Flt morpholinos decrease mFlt-1 and increase sFlt-1 levels, resulting in decreased neovascularization in a murine corneal suture model.

Cited by 13 publications

References 30 publications

Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis

Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis

Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1

Gene Therapy in Corneal Transplantation

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