Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Abstract 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 poorl...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45456-z |
| _version_ | 1797273991364214784 |
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| author | Thomas L. Maurissen Alena J. Spielmann Gabriella Schellenberg Marc Bickle Jose Ricardo Vieira Si Ying Lai Georgios Pavlou Sascha Fauser Peter D. Westenskow Roger D. Kamm Héloïse Ragelle |
| author_facet | Thomas L. Maurissen Alena J. Spielmann Gabriella Schellenberg Marc Bickle Jose Ricardo Vieira Si Ying Lai Georgios Pavlou Sascha Fauser Peter D. Westenskow Roger D. Kamm Héloïse Ragelle |
| author_sort | Thomas L. Maurissen |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T14:52:03Z |
| format | Article |
| id | doaj.art-ec45dba5d88548cbb695e377fc41e056 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:03Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ec45dba5d88548cbb695e377fc41e0562024-03-05T19:41:09ZengNature PortfolioNature Communications2041-17232024-02-0115111310.1038/s41467-024-45456-zModeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chipThomas L. Maurissen0Alena J. Spielmann1Gabriella Schellenberg2Marc Bickle3Jose Ricardo Vieira4Si Ying Lai5Georgios Pavlou6Sascha Fauser7Peter D. Westenskow8Roger D. Kamm9Héloïse Ragelle10Roche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Institute of Human Biology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdDepartment of Biological Engineering, Massachusetts Institute of TechnologyRoche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdDepartment of Biological Engineering, Massachusetts Institute of TechnologyRoche Pharma Research and Early Development, Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche LtdAbstract 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.https://doi.org/10.1038/s41467-024-45456-z |
| spellingShingle | Thomas L. Maurissen Alena J. Spielmann Gabriella Schellenberg Marc Bickle Jose Ricardo Vieira Si Ying Lai Georgios Pavlou Sascha Fauser Peter D. Westenskow Roger D. Kamm Héloïse Ragelle Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip Nature Communications |
| title | Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip |
| title_full | Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip |
| title_fullStr | Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip |
| title_full_unstemmed | Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip |
| title_short | Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip |
| title_sort | modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood retinal barrier on a chip |
| url | https://doi.org/10.1038/s41467-024-45456-z |
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