Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip.

Autor: Maurissen TL; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Spielmann AJ; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Schellenberg G; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Bickle M; Roche Pharma Research and Early Development, Institute of Human Biology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Vieira JR; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Lai SY; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Pavlou G; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Fauser S; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Westenskow PD; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Kamm RD; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. rdkamm@mit.edu.; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. rdkamm@mit.edu., Ragelle H; Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. heloise.ragelle@roche.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 14; Vol. 15 (1), pp. 1372. Date of Electronic Publication: 2024 Feb 14.
DOI: 10.1038/s41467-024-45456-z
Abstrakt: Diabetic retinopathy (DR) is a microvascular disorder characterized by inner blood-retinal barrier (iBRB) breakdown and irreversible vision loss. While the symptoms of DR are known, disease mechanisms including basement membrane thickening, pericyte dropout and capillary damage remain poorly understood and interventions to repair diseased iBRB microvascular networks have not been developed. In addition, current approaches using animal models and in vitro systems lack translatability and predictivity to finding new target pathways. Here, we develop a diabetic iBRB-on-a-chip that produces pathophysiological phenotypes and disease pathways in vitro that are representative of clinical diagnoses. We show that diabetic stimulation of the iBRB-on-a-chip mirrors DR features, including pericyte loss, vascular regression, ghost vessels, and production of pro-inflammatory factors. We also report transcriptomic data from diabetic iBRB microvascular networks that may reveal drug targets, and examine pericyte-endothelial cell stabilizing strategies. In summary, our model recapitulates key features of disease, and may inform future therapies for DR.
(© 2024. The Author(s).)
Databáze: MEDLINE
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