1. In-Depth Molecular Characterization of Neovascular Membranes Suggests a Role for Hyalocyte-to-Myofibroblast Transdifferentiation in Proliferative Diabetic Retinopathy
- Author
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Stefaniya Konstantinova Boneva, Julian Wolf, Rozina Ida Hajdú, Gabriele Prinz, Henrike Salié, Anja Schlecht, Saskia Killmer, Yannik Laich, Henrik Faatz, Albrecht Lommatzsch, Martin Busch, Felicitas Bucher, Andreas Stahl, Daniel Böhringer, Bertram Bengsch, Günther Schlunck, Hansjürgen Agostini, and Clemens A. K. Lange
- Subjects
Male ,Pathology ,transdifferentiation ,retinal neovascularization (RNV) ,Retinal Neovascularization ,Pathogenesis ,Immunology and Allergy ,Medicine ,Cells, Cultured ,Original Research ,medicine.diagnostic_test ,Transdifferentiation ,Imaging Mass Cytometry ,Epiretinal Membrane ,RNA sequencing ,Diabetic retinopathy ,Middle Aged ,Imatinib Mesylate ,Immunohistochemistry ,Female ,Hyalocyte ,Single-Cell Analysis ,Myofibroblast ,Adult ,medicine.medical_specialty ,myofibroblasts ,Immunology ,proliferative diabetic retinopathy (PDR) ,Flow cytometry ,hyalocytes ,Young Adult ,Humans ,Immunologic Factors ,Mass cytometry ,Eye Proteins ,Aged ,Diabetic Retinopathy ,business.industry ,Drug Repositioning ,Computational Biology ,Endothelial Cells ,RC581-607 ,Retinal Perforations ,medicine.disease ,eye diseases ,Vitreous Body ,Gene Ontology ,Cell Transdifferentiation ,sense organs ,Immunologic diseases. Allergy ,Transcriptome ,business - Abstract
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.
- Published
- 2021