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

Guillermo L Lehmann; Christin Hanke-Gogokhia; Yang Hu; Rohan Bareja; Zelda Salfati; Michael Ginsberg; Daniel J Nolan; Santiago P Mendez-Huergo; Tomas Dalotto-Moreno; Alexandre Wojcinski; Francisca Ochoa; Shemin Zeng; Juan P Cerliani; Lampros Panagis; Patrick J Zager; Robert F Mullins; Shuntaro Ogura; Gerard A Lutty; Jakyung Bang; Jonathan H Zippin; Carmelo Romano; Gabriel A Rabinovich; Olivier Elemento; Alexandra L Joyner; Shahin Rafii; Enrique Rodriguez-Boulan; Ignacio Benedicto

doi:10.1084/jem.20190730

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

Journal article

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

Guillermo L Lehmann, Christin Hanke-Gogokhia, Yang Hu, Rohan Bareja, Zelda Salfati, Michael Ginsberg, Daniel J Nolan, Santiago P Mendez-Huergo, Tomas Dalotto-Moreno, Alexandre Wojcinski, …

The Journal of experimental medicine, Vol.217(6), e20190730

06/01/2020

DOI: 10.1084/jem.20190730

PMCID: PMC7971135

PMID: 32196081

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Abstract

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.

Signal Transduction

Animals

Cell Proliferation

Choroid - immunology

Choroid - pathology

Endothelial Cells - metabolism

Endothelium - immunology

Gene Expression Regulation

Hedgehog Proteins - metabolism

Immunomodulation

Inflammation - genetics

Mast Cells - metabolism

Melanocytes - metabolism

Melanocytes - pathology

Mice, Inbred C57BL

Organ Specificity

Retinal Pigment Epithelium - metabolism

Single-Cell Analysis

Transcription, Genetic

Zinc Finger Protein GLI1 - metabolism

Details

Title: Subtitle: Single-cell profiling reveals an endothelium-mediated immunomodulatory pathway in the eye choroid
Creators: Guillermo L Lehmann - Regeneron (United States)
Christin Hanke-Gogokhia - Weill Cornell Medicine
Yang Hu - Cornell University
Rohan Bareja - Cornell University
Zelda Salfati - Cornell University
Michael Ginsberg - Angiocrine Bioscience (United States)
Daniel J Nolan - Angiocrine Bioscience (United States)
Santiago P Mendez-Huergo - Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Tomas Dalotto-Moreno - Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Alexandre Wojcinski - Memorial Sloan Kettering Cancer Center
Francisca Ochoa - Regeneron (United States)
Shemin Zeng - University of Iowa
Juan P Cerliani - Instituto de Biología y Medicina Experimental
Lampros Panagis - Regeneron (United States)
Patrick J Zager - Cornell University
Robert F Mullins - University of Iowa
Shuntaro Ogura - Johns Hopkins University
Gerard A Lutty - Johns Hopkins University
Jakyung Bang - Weill Cornell Medicine
Jonathan H Zippin - Weill Cornell Medicine
Carmelo Romano - Regeneron (United States)
Gabriel A Rabinovich - Facultad de Ciencias Exactas y Naturales
Olivier Elemento - Cornell University
Alexandra L Joyner - Memorial Sloan Kettering Cancer Center
Shahin Rafii - Cornell University
Enrique Rodriguez-Boulan - Weill Cornell Medicine
Ignacio Benedicto - Cornell University
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.217(6), e20190730
DOI: 10.1084/jem.20190730
PMID: 32196081
PMCID: PMC7971135
NLM abbreviation: J Exp Med
ISSN: 0022-1007
eISSN: 1540-9538
Grant note: U24 CA210989 / NCI NIH HHS R21 CA224391 / NCI NIH HHS R01 EY008538 / NEI NIH HHS R01 GM034107 / NIGMS NIH HHS P50 CA211024 / NCI NIH HHS R01 CA192176 / NCI NIH HHS P30 CA008748 / NCI NIH HHS R01 CA194547 / NCI NIH HHS
Language: English
Date published: 06/01/2020
Academic Unit: Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9984182972602771

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