Epithelial Membrane Protein-2 (EMP2) Antibody Blockade Reduces Corneal Neovascularization in an In Vivo Model

Sun, Michel M.; Chan, Ann M.; Law, Samuel M.; Duarte, Sergio; Diaz-Aguilar, Daniel; Wadehra, Madhuri; Gordon, Lynn K.

doi:10.1167/iovs.18-24345

Cited by 15 publications

(17 citation statements)

References 69 publications

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“…Under normal conditions, corneal epithelial [[22], [23], [24], [25]] and stromal [21,23,25,26] cells have been reported to either promote or inhibit neovascularization. Moreover, under inflammation conditions, corneal epithelial cells have been reported to mediate neovascularization through a paracrine mechanism via VEGF-A [5,27] and epithelial membrane protein-2 [28], whereas corneal stromal cells have been reported to mediate neovascularization through a paracrine mechanism via VEGF-A [5,27], transforming growth factor β [[29], [30], [31], [32]], and MMP-13 [33]. However, the key proteins produced by corneal host epithelial and stromal cells leading to neovascularization have not yet been determined, such that the mechanism of corneal endothelial cells involved in neovascularization remains largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Three kinds of corneal host cells contribute differently to corneal neovascularization

Sun

Cui

et al. 2019

eBioMedicine

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Background Corneal neovascularization (angiogenesis and lymphangiogenesis) compromises corneal transparency and transplant survival, however, the molecular mechanisms of corneal host epithelial and stromal cells in neovascularization have not yet been fully elucidated. Furthermore, the contribution and mechanism of corneal host endothelial cells involved in neovascularization are largely unexplored. Methods Liquid chromatography-mass spectrometry, immunoblotting, and ELISA were used to screen and identify potential neovascularization-related factors in human full-thickness vascularized corneal tissues. Lipopolysaccharide was used to induce inflammation in three kinds of corneal host cells in vitro , including corneal epithelial, stromal, and endothelial cells. Fungus was used to establish an animal model of corneal neovascularization in vivo . Tube formation and spheroid sprouting assays were used to evaluate the contribution of three kinds of corneal host cells to the degree of neovascularization under various stimuli. Matrix metalloproteinase (MMP)-2, alpha-crystallin A chain (CRYAA), galectin-8, Bcl-2, neuropilin-2, MMP-9 plasmids, and recombinant human fibronectin were used to identify the key proteins of corneal host cells involved in corneal inflammatory neovascularization. Findings All three kinds of corneal host cells influenced corneal neovascularization to varying degrees. MMP-9 in human corneal epithelial cells, MMP-2, and CRYAA in human corneal stromal cells, and MMP-2 and galectin-8 in human corneal endothelial cells are potential key proteins that participate in corneal inflammatory neovascularization. Interpretation Our data indicated that both the effects of key proteins and corneal host cells involved should be considered for the treatment of corneal inflammatory neovascularization.

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Section: Introductionmentioning

confidence: 99%

Three kinds of corneal host cells contribute differently to corneal neovascularization

Sun

Cui

et al. 2019

eBioMedicine

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“…EMP2 has been previously linked to angiogenesis through both VEGF-dependent and VEGF-independent pathways in multiple tumor models (21, 23). In addition to tumorigenesis, alterations in EMP2 expression has now been linked to failure of appropriate placental angiogenesis and pathogenic corneal neovascularization (26, 35). EMP2 is currently being investigated as a novel target for cancer treatment and to reduce pathologic neovascularization (23, 24, 35–37).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to tumorigenesis, alterations in EMP2 expression has now been linked to failure of appropriate placental angiogenesis and pathogenic corneal neovascularization (26, 35). EMP2 is currently being investigated as a novel target for cancer treatment and to reduce pathologic neovascularization (23, 24, 35–37). As such, it is essential to further define the role of EMP2 in the vasculature as well as other tissues.…”

Section: Discussionmentioning

confidence: 99%

Genetic Deletion of Emp2 Does Not Cause Proteinuric Kidney Disease in Mice

et al. 2019

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Nephrotic syndrome is one of the most common glomerular diseases in children and can be classified on the basis of steroid responsiveness. While multiple genetic causes have been discovered for steroid resistant nephrotic syndrome, the genetics of steroid sensitive nephrotic syndrome remains elusive. Mutations in Epithelial Membrane Protein 2 ( EMP2 ), a member of the GAS3/PMP22 tetraspan family of proteins, were recently implicated as putative monogenic cause of steroid sensitive nephrotic syndrome. We investigated this hypothesis by developing Emp2 reporter and knockout mouse models. In lacZ reporter mice (engineered to drive expression of the enzyme β-galactosidase under the control of the endogenous murine Emp2 promoter), Emp2 promoter activity was not observed in podocytes but was particularly prominent in medium- and large-caliber arterial vessels in the kidney and other tissues where it localizes specifically in vascular smooth muscle cells (vSMCs) but not in the endothelium. Strong Emp2 expression was also found in non-vascular smooth muscle cells found in other organs like the stomach, bladder, and uterus. Global and podocyte-specific Emp2 knockout mice were viable and did not develop nephrotic syndrome showing no evidence of abnormal glomerular histology or ultrastructure. Altogether, our results do not support that loss of function of EMP2 represent a monogenic cause of proteinuric kidney disease. However, the expression pattern of Emp2 indicates that it may be relevant in smooth muscle function in various organs and tissues including the vasculature.

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“…Several animal models have been established to study corneal burn injuries. These models generally use a NaOH solution (1 N), which is directly applied to the center of the corneal surface in animals for 15-60 s [53][54][55][56]60,61,63]. Similar to the process in humans, the process of corneal alkali burn healing in animal models involves immediate local inflammation followed by fibrosis and neovascularization.…”

Section: Corneamentioning

confidence: 99%

“…A rabbit model of chemical corneal burns indicated the role of limbal stem cells in the initiation of neovascularization after burn injury [54]. In a mouse corneal burn model, corneal-limbal epithelial membrane protein-2 (EMP2) was identified as a promoter of pathological corneal neovascularization [60]. Studies using another mouse model showed that galectin-3 enhances corneal angiogenesis by modulating VEGF/VEGFR-2 signaling [59].…”

Section: Corneal Neovascularizationmentioning

confidence: 99%

Recent Advances in Experimental Burn Models

Hao

Nourbakhsh

2021

Biology

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Experimental burn models are essential tools for simulating human burn injuries and exploring the consequences of burns or new treatment strategies. Unlike clinical studies, experimental models allow a direct comparison of different aspects of burns under controlled conditions and thereby provide relevant information on the molecular mechanisms of tissue damage and wound healing, as well as potential therapeutic targets. While most comparative burn studies are performed in animal models, a few human or humanized models have been successfully employed to study local events at the injury site. However, the consensus between animal and human studies regarding the cellular and molecular nature of systemic inflammatory response syndrome (SIRS), scarring, and neovascularization is limited. The many interspecies differences prohibit the outcomes of animal model studies from being fully translated into the human system. Thus, the development of more targeted, individualized treatments for burn injuries remains a major challenge in this field. This review focuses on the latest progress in experimental burn models achieved since 2016, and summarizes the outcomes regarding potential methodological improvements, assessments of molecular responses to injury, and therapeutic advances.

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Epithelial Membrane Protein-2 (EMP2) Antibody Blockade Reduces Corneal Neovascularization in an In Vivo Model

Cited by 15 publications

References 69 publications

Three kinds of corneal host cells contribute differently to corneal neovascularization

Three kinds of corneal host cells contribute differently to corneal neovascularization

Genetic Deletion of Emp2 Does Not Cause Proteinuric Kidney Disease in Mice

Recent Advances in Experimental Burn Models

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