Single-cell profiling reveals an endothelium-mediated immunomodulatory pathway in the eye choroid

The activity and survival of retinal photoreceptors depend on support functions performed by the retinal pigment epithelium (RPE) and on oxygen and nutrients delivered by blood vessels in the underlying choroid. By combining single-cell and bulk RNA sequencing, we categorized mouse RPE/choroid cell...

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Bibliographic Details
Published in:The Journal of experimental medicine 2020-06, Vol.217 (6)
Main Authors: Lehmann, Guillermo L, Hanke-Gogokhia, Christin, Hu, Yang, Bareja, Rohan, Salfati, Zelda, Ginsberg, Michael, Nolan, Daniel J, Mendez-Huergo, Santiago P, Dalotto-Moreno, Tomas, Wojcinski, Alexandre, Ochoa, Francisca, Zeng, Shemin, Cerliani, Juan P, Panagis, Lampros, Zager, Patrick J, Mullins, Robert F, Ogura, Shuntaro, Lutty, Gerard A, Bang, Jakyung, Zippin, Jonathan H, Romano, Carmelo, Rabinovich, Gabriel A, Elemento, Olivier, Joyner, Alexandra L, Rafii, Shahin, Rodriguez-Boulan, Enrique, Benedicto, Ignacio
Format: Article
Language:English
Subjects:
Animals
Cardiovascular Biology
Cell Proliferation
Choroid - immunology
Choroid - pathology
Endothelial Cells - metabolism
Endothelium - immunology
Gene Expression Regulation
Hedgehog Proteins - metabolism
Immunomodulation
Inflammation - genetics
Innate immunity and inflammation
Mast Cells - metabolism
Melanocytes - metabolism
Melanocytes - pathology
Mice, Inbred C57BL
Organ Specificity
Retinal Pigment Epithelium - metabolism
Signal Transduction
Single-Cell Analysis
Transcription, Genetic
Zinc Finger Protein GLI1 - metabolism
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Summary:The activity and survival of retinal photoreceptors depend on support functions performed by the retinal pigment epithelium (RPE) and on oxygen and nutrients delivered by blood vessels in the underlying choroid. By combining single-cell and bulk RNA sequencing, we categorized mouse RPE/choroid cell types and characterized the tissue-specific transcriptomic features of choroidal endothelial cells. We found that choroidal endothelium adjacent to the RPE expresses high levels of Indian Hedgehog and identified its downstream target as stromal GLI1+ mesenchymal stem cell-like cells. In vivo genetic impairment of Hedgehog signaling induced significant loss of choroidal mast cells, as well as an altered inflammatory response and exacerbated visual function defects after retinal damage. Our studies reveal the cellular and molecular landscape of adult RPE/choroid and uncover a Hedgehog-regulated choroidal immunomodulatory signaling circuit. These results open new avenues for the study and treatment of retinal vascular diseases and choroid-related inflammatory blinding disorders.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20190730