Collagen-producing eye cell atlas reveals distinct fibroblast fates in early injury vs. fibrotic subretinal disease
Abstract
Fibrosis is the end-stage of a maladaptive process that occurs when the body’s normal wound-healing strategy becomes dysregulated. Subretinal fibrosis is the end stage of neovascular age-related macular degeneration (nAMD), the most common cause of central vision loss in people over the age of 50. The cellular sources of excess extracellular matrix (ECM) contributing to subretinal fibrosis are unknown, as is the heterogeneity of cells involved in the fibrotic process. Here we identify cells contributing to subretinal fibrosis by using Col1a1 -YFP reporter mice to noninvasively image collagen production in real-time in vivo in two disease models, 1) a resolving retinal injury model and 2) a fibrotic model of subretinal disease. We create a collagen-producing eye cell atlas for subretinal injury and demonstrate subretinal fibroblast heterogeneity in healthy, resolving, and fibrotic tissue. We identify distinct molecular characteristics of general repair/resolving fibroblast populations versus pathogenic pro-fibrotic collagen-producing fibroblasts. Integration of this collagen-producing eye cell atlas with a published collagen-producing lung cell atlas shows conserved pro-fibrotic fibroblasts in both organs, yet also uncovers tissue-specific fibroblast populations unique to subretinal fibrosis. A Fap + Fgl2 + fibroblast population significantly expands in subretinal fibrosis that expresses the highest levels of collagens and distinctively expresses ECM components Periostin , Col15a1 and Col6a5 . Immunolabeling of mouse and human-donor eye tissue support the fibroblastic expression and perivascular location of periostin as clearly distinguishing between bona fide fibrosis and early disease in nAMD. Our collagen-producing eye cell atlas is a valuable resource for studying distinct fibroblast subsets in homeostasis, early injury, and fibrosis.
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BibTeX
@article{ozaki2026collagenproducing,
title = {{Collagen-producing eye cell atlas reveals distinct fibroblast fates in early injury vs. fibrotic subretinal disease}},
author = {Ema Ozaki and Said Aktas and Kelly Mulfaul and Kiva Brennan and Christo Roubeix and Sarah Palko and Katie Robb and Tai-Hsien Ou and Marie-Claire Schanne-Klein and Anna Toidze and Avril Watson and Mark Cahill and Peter Westenskow and Derrick Feenstra and Sarah L Doyle and Napoleone Ferrara},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = jun,
doi = {10.1073/pnas.2519056123},
url = {https://hal.science/hal-05733343v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Collagen-producing eye cell atlas reveals distinct fibroblast fates in early injury vs. fibrotic subretinal disease
AU - Ema Ozaki
AU - Said Aktas
AU - Kelly Mulfaul
AU - Kiva Brennan
AU - Christo Roubeix
AU - Sarah Palko
AU - Katie Robb
AU - Tai-Hsien Ou
AU - Marie-Claire Schanne-Klein
AU - Anna Toidze
AU - Avril Watson
AU - Mark Cahill
AU - Peter Westenskow
AU - Derrick Feenstra
AU - Sarah L Doyle
AU - Napoleone Ferrara
PY - 2026
DA - 2026/06/26
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2519056123
UR - https://hal.science/hal-05733343v1
AB - Fibrosis is the end-stage of a maladaptive process that occurs when the body’s normal wound-healing strategy becomes dysregulated. Subretinal fibrosis is the end stage of neovascular age-related macular degeneration (nAMD), the most common cause of central vision loss in people over the age of 50. The cellular sources of excess extracellular matrix (ECM) contributing to subretinal fibrosis are unknown, as is the heterogeneity of cells involved in the fibrotic process. Here we identify cells contributing to subretinal fibrosis by using Col1a1 -YFP reporter mice to noninvasively image collagen production in real-time in vivo in two disease models, 1) a resolving retinal injury model and 2) a fibrotic model of subretinal disease. We create a collagen-producing eye cell atlas for subretinal injury and demonstrate subretinal fibroblast heterogeneity in healthy, resolving, and fibrotic tissue. We identify distinct molecular characteristics of general repair/resolving fibroblast populations versus pathogenic pro-fibrotic collagen-producing fibroblasts. Integration of this collagen-producing eye cell atlas with a published collagen-producing lung cell atlas shows conserved pro-fibrotic fibroblasts in both organs, yet also uncovers tissue-specific fibroblast populations unique to subretinal fibrosis. A Fap + Fgl2 + fibroblast population significantly expands in subretinal fibrosis that expresses the highest levels of collagens and distinctively expresses ECM components Periostin , Col15a1 and Col6a5 . Immunolabeling of mouse and human-donor eye tissue support the fibroblastic expression and perivascular location of periostin as clearly distinguishing between bona fide fibrosis and early disease in nAMD. Our collagen-producing eye cell atlas is a valuable resource for studying distinct fibroblast subsets in homeostasis, early injury, and fibrosis.
SN - 0027-8424
SN - 1091-6490
ER -