scholarly journals In-Depth Molecular Characterization of Neovascular Membranes Suggests a Role for Hyalocyte-to-Myofibroblast Transdifferentiation in Proliferative Diabetic Retinopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Stefaniya Konstantinova Boneva ◽  
Julian Wolf ◽  
Rozina Ida Hajdú ◽  
Gabriele Prinz ◽  
Henrike Salié ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Single Cell ◽  
Proliferative Diabetic Retinopathy ◽  
Drug Repurposing ◽  
Cell Protein ◽  
Tissue Samples ◽  
Epiretinal Membranes ◽  
Vitreoretinal Disease ◽  
End Stage

BackgroundRetinal neovascularization (RNV) membranes can lead to a tractional retinal detachment, the primary reason for severe vision loss in end-stage disease proliferative diabetic retinopathy (PDR). The aim of this study was to characterize the molecular, cellular and immunological features of RNV in order to unravel potential novel drug treatments for PDR.MethodsA total of 43 patients undergoing vitrectomy for PDR, macular pucker or macular hole (control patients) were included in this study. The surgically removed RNV and epiretinal membranes were analyzed by RNA sequencing, single-cell based Imaging Mass Cytometry and conventional immunohistochemistry. Immune cells of the vitreous body, also known as hyalocytes, were isolated from patients with PDR by flow cytometry, cultivated and characterized by immunohistochemistry. A bioinformatical drug repurposing approach was applied in order to identify novel potential drug options for end-stage diabetic retinopathy disease.ResultsThe in-depth transcriptional and single-cell protein analysis of diabetic RNV tissue samples revealed an accumulation of endothelial cells, macrophages and myofibroblasts as well as an abundance of secreted ECM proteins such as SPARC, FN1 and several types of collagen in RNV tissue. The immunohistochemical staining of cultivated vitreal hyalocytes from patients with PDR showed that hyalocytes express α-SMA (alpha-smooth muscle actin), a classic myofibroblast marker. According to our drug repurposing analysis, imatinib emerged as a potential immunomodulatory drug option for future treatment of PDR.ConclusionThis study delivers the first in-depth transcriptional and single-cell proteomic characterization of RNV tissue samples. Our data suggest an important role of hyalocyte-to-myofibroblast transdifferentiation in the pathogenesis of diabetic vitreoretinal disease and their modulation as a novel possible clinical approach.

Impact and Characterization of Delayed Pan-Retinal Photocoagulation in Proliferative Diabetic Retinopathy

2021 ◽  
Vol 223 ◽  
pp. 267-274
Author(s):  
Marc Ohlhausen ◽  
Carter Payne ◽  
Tyler Greenlee ◽  
Andrew X. Chen ◽  
Thais Conti ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Proliferative Diabetic Retinopathy ◽  
Pan Retinal Photocoagulation ◽  
Retinal Photocoagulation

Transcription factor, SP1, in epiretinal membranes of patients with proliferative diabetic retinopathy

2010 ◽  
Vol 87 (3) ◽  
pp. e26-e28 ◽  
Author(s):  
Natsuyo Yoshida-Hata ◽  
Yoshinori Mitamura ◽  
Toshiyuki Oshitari ◽  
Kazuhiko Namekata ◽  
Chikako Harada ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Diabetic Retinopathy ◽  
Proliferative Diabetic Retinopathy ◽  
Epiretinal Membranes ◽  
Transcription Factor Sp1

scholarly journals Evaluation of Proteoforms of the Transmembrane Chemokines CXCL16 and CX3CL1, Their Receptors, and Their Processing Metalloproteinases ADAM10 and ADAM17 in Proliferative Diabetic Retinopathy

2021 ◽  
Vol 11 ◽  
Author(s):  
Ahmed M. Abu El-Asrar ◽  
Mohd Imtiaz Nawaz ◽  
Ajmal Ahmad ◽  
Alexandra De Zutter ◽  
Mohammad Mairaj Siddiquei ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Blood Vessels ◽  
Proliferative Diabetic Retinopathy ◽  
Müller Cells ◽  
Intercellular Adhesion Molecule ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diabetic Patients ◽  
Muller Cells ◽  
Epiretinal Membranes ◽  
Positive Correlations

The transmembrane chemokine pathways CXCL16/CXCR6 and CX3CL1/CX3CR1 are strongly implicated in inflammation and angiogenesis. We investigated the involvement of these chemokine pathways and their processing metalloproteinases ADAM10 and ADAM17 in the pathophysiology of proliferative diabetic retinopathy (PDR). Vitreous samples from 32 PDR and 24 non-diabetic patients, epiretinal membranes from 18 patients with PDR, rat retinas, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by enzyme-linked immunosorbent assay, immunohistochemistry and Western blot analysis. In vitro angiogenesis assays were performed and the adherence of leukocytes to CXCL16-stimulated HRMECs was assessed. CXCL16, CX3CL1, ADAM10, ADAM17 and vascular endothelial growth factor (VEGF) levels were significantly increased in vitreous samples from PDR patients. The levels of CXCL16 were 417-fold higher than those of CX3CL1 in PDR vitreous samples. Significant positive correlations were found between the levels of VEGF and the levels of CXCL16, CX3CL1, ADAM10 and ADAM17. Significant positive correlations were detected between the numbers of blood vessels expressing CD31, reflecting the angiogenic activity of PDR epiretinal membranes, and the numbers of blood vessels and stromal cells expressing CXCL16, CXCR6, ADAM10 and ADAM17. CXCL16 induced upregulation of phospho-ERK1/2, p65 subunit of NF-κB and VEGF in cultured Müller cells and tumor necrosis factor-α induced upregulation of soluble CXCL16 and ADAM17 in Müller cells. Treatment of HRMECs with CXCL16 resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and increased leukocyte adhesion to HRMECs. CXCL16 induced HRMEC proliferation, formation of sprouts from HRMEC spheroids and phosphorylation of ERK1/2. Intravitreal administration of CXCL16 in normal rats induced significant upregulation of the p65 subunit of NF-κB, VEGF and ICAM-1 in the retina. Our findings suggest that the chemokine axis CXCL16/CXCR6 and the processing metalloproteinases ADAM10 and ADAM17 might serve a role in the initiation and progression of PDR.

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