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Topological Analysis of Single-Cell Hierarchy Reveals Inflammatory Glial Landscape of Macular Degeneration

51 Pages Posted: 29 Sep 2021 Publication Status: Review Complete

See all articles by Manik Kuchroo

Manik Kuchroo

Yale University - Department of Neuroscience; Yale University - Department of Genetics and Computer Science

Marcello DiStasio

Yale University - Department of Pathology

Eric Song

Yale University - Department of Ophthalmology and Visual Science

Eda Calapkulu

Yale University - Department of Ophthalmology and Visual Science

Le Zhang

Yale University - Department of Neurology

Maryam Ige

Yale University - School of Medicine

Amar H. Sheth

Yale University - School of Medicine

Madhvi Menon

University of Manchester - Division of Infection, Immunity and Respiratory Medicine; University of Manchester - Lydia Becker Institute of Immunology and Inflammation

Alexander Tong

Yale University - Department of Computer Science

Abhinav Godavarthi

Yale University - Department of Applied Mathematics

Yu Xing

Yale University - Department of Ophthalmology and Visual Science

Scott Gigante

Yale University - Computational Biology

Holly Steach

Yale University - Department of Immunobiology

Jessie Huang

Yale University - Department of Computer Science

Guillaume Huguet

Mila - Quebec AI Institute

Janhavi Narain

Rutgers University, New Brunswick - Department of Computer Science

George Mourgkos

Yale University - Department of Pathology

Rahul M. Dhodapkar

Yale University - School of Medicine

Matthew J. Hirn

Michigan State University - Department of Computational Mathematics, Science and Engineering; Michigan State University

Bastian Rieck

ETH Zürich - Department of Biosystems Science and Engineering

Guy Wolf

Mila - Quebec AI Institute; Yale University - Applied Mathematics Program

Smita Krishnaswamy

Mila - Quebec AI Institute; Yale University - Department of Computer Science; Yale University - Department of Genetics

Brian P. Hafler

Yale University - Department of Pathology

More...

Abstract

Age-related macular degeneration (AMD) is a degenerative disease of the retina with unknown cellular drivers.  To identify, characterize, and compare rare pathogenic clusters of cells, we developed CATCH, a coarse graining framework that learns the cellular hierarchy. CATCH includes a suite of tools that identify salient levels of the hierarchy, automatically characterize clusters, identify pathogenic populations, and rapidly compute differentially expressed genes. We applied CATCH to the first single-cell atlas of AMD and identified two populations of activated glia enriched in the early phase of disease, one microglial and one astrocyte. Applying CATCH to other degenerative diseases revealed the same activated states in early disease, indicating a common glial signature during early neurodegeneration. In late-stage AMD, CATCH identified a microglia-to-astrocyte signaling axis mediated by IL-1β which drives VEGFA expression and pathologic angiogenesis. We validated this mechanism using in vitro and in vivo assays, identifying a new therapeutic target for AMD.

Keywords: retina, neurodegeneration, age-related macular degeneration, manifold learning, data-diffusion, clustering, single-cell transcriptomics, machine learning, glia, earth mover's distance

Suggested Citation

Kuchroo, Manik and Kuchroo, Manik and DiStasio, Marcello and Song, Eric and Calapkulu, Eda and Zhang, Le and Ige, Maryam and Sheth, Amar H. and Menon, Madhvi and Menon, Madhvi and Tong, Alexander and Godavarthi, Abhinav and Xing, Yu and Gigante, Scott and Steach, Holly and Huang, Jessie and Huguet, Guillaume and Narain, Janhavi and Mourgkos, George and Dhodapkar, Rahul M. and Hirn, Matthew J. and Hirn, Matthew J. and Rieck, Bastian and Wolf, Guy and Wolf, Guy and Krishnaswamy, Smita and Krishnaswamy, Smita and Krishnaswamy, Smita and Hafler, Brian P., Topological Analysis of Single-Cell Hierarchy Reveals Inflammatory Glial Landscape of Macular Degeneration. Available at SSRN: https://ssrn.com/abstract=3933294 or http://dx.doi.org/10.2139/ssrn.3933294
This version of the paper has not been formally peer reviewed.

Manik Kuchroo

Yale University - Department of Genetics and Computer Science ( email )

333 Cedar Street
New Haven, CT 06520
United States

Yale University - Department of Neuroscience ( email )

200 S Frontage Rd
New Haven, CT 06510
United States

Marcello DiStasio

Yale University - Department of Pathology ( email )

310 Cedar Street LH 108
PO Box 208023
New Haven, CT 06520
United States

Eric Song

Yale University - Department of Ophthalmology and Visual Science

New Haven, CT
United States

Eda Calapkulu

Yale University - Department of Ophthalmology and Visual Science ( email )

New Haven, CT
United States

Le Zhang

Yale University - Department of Neurology

New Haven, CT
United States

Maryam Ige

Yale University - School of Medicine ( email )

333 Cedar Street
New Haven, CT 06520-8034
United States

Amar H. Sheth

Yale University - School of Medicine ( email )

333 Cedar Street
New Haven, CT 06520-8034
United States

Madhvi Menon

University of Manchester - Division of Infection, Immunity and Respiratory Medicine ( email )

Manchester
United Kingdom

University of Manchester - Lydia Becker Institute of Immunology and Inflammation ( email )

United Kingdom

Alexander Tong

Yale University - Department of Computer Science ( email )

P.O. Box 208285
New Haven, CT
United States

Abhinav Godavarthi

Yale University - Department of Applied Mathematics ( email )

New Haven, CT 06520
United States

Yu Xing

Yale University - Department of Ophthalmology and Visual Science

New Haven, CT
United States

Scott Gigante

Yale University - Computational Biology ( email )

New Haven, CT 06520
United States

Holly Steach

Yale University - Department of Immunobiology ( email )

300 Cedar Street
New Haven, CT 06520
United States

Jessie Huang

Yale University - Department of Computer Science

P.O. Box 208285
New Haven, CT
United States

Guillaume Huguet

Mila - Quebec AI Institute

Quebec
Canada

Janhavi Narain

Rutgers University, New Brunswick - Department of Computer Science ( email )

New Brunswick, NJ
United States

George Mourgkos

Yale University - Department of Pathology ( email )

310 Cedar Street LH 108
PO Box 208023
New Haven, CT 06520
United States

Rahul M. Dhodapkar

Yale University - School of Medicine ( email )

333 Cedar Street
New Haven, CT 06520-8034
United States

Matthew J. Hirn

Michigan State University - Department of Computational Mathematics, Science and Engineering ( email )

East Lansing, MI
United States

Michigan State University

Agriculture Hall
East Lansing, MI 48824-1122
United States

Bastian Rieck

ETH Zürich - Department of Biosystems Science and Engineering ( email )

Mattenstrasse 26
4058 Basel
Zürich, 8092
Switzerland

Guy Wolf

Yale University - Applied Mathematics Program

51 Prospect Street
New Haven, CT 06511
United States

Mila - Quebec AI Institute

Quebec
Canada

Smita Krishnaswamy (Contact Author)

Yale University - Department of Computer Science ( email )

P.O. Box 208285
New Haven, CT
United States

Yale University - Department of Genetics ( email )

333 Cedar Street
New Haven, CT 06520
United States

Mila - Quebec AI Institute

Quebec
Canada

Brian P. Hafler

Yale University - Department of Pathology ( email )

310 Cedar Street LH 108
PO Box 208023
New Haven, CT 06520
United States

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