TGFb signaling instructs a conserved fibrosis-associated cell state marked by LRRC15
Abstract
Fibroblasts are key potentiators of chronic disease pathophysiology. Despite their established roles in promoting pathological inflammation and tissue remodeling, activated myofibroblasts are generally characterized as a single, homogeneous cell population, obscuring critical functional distinctions. Defining the cell states, their molecular regulators, and restricted markers is critical to developing effective therapies for the treatment of fibrosis. Here, using a human lung stromal cell atlas of idiopathic pulmonary fibrosis, we identify two myofibroblast transcriptional states associated with distinct predicted biological function, regulation, and cell surface marker expression. We identify fibroblast-specific TGFb signaling as the key regulator of the mechanistic switch from a wound healing–associated and proliferative to a profibrotic myofibroblast. Further, we elucidate conserved TGFb-dependent and suppressed gene expression programs that define these states. Our findings reveal that LRRC15 is highly restricted to myofibroblasts that primarily express an extracellular matrix-remodeling gene program and illuminate that this key cell state can differentiate in the absence of an obligate inflammatory precursor intermediate. Last, we apply machine learning using a human single-cell foundation model to demonstrate broad applicability of the biology described herein to human chronic disease.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (35)
Justin A. Shyer
Genentech Research and Early Development, Genentech, Inc.
Fabien Wehbe
Roche Informatics, F. Hoffmann-La Roche Ltd.
Christopher D. Davidson
Genentech Research and Early Development, Genentech, Inc.
Hannah S. Bender
Genentech Research and Early Development, Genentech, Inc.
Minh Thai
Genentech Research and Early Development, Genentech, Inc.
Christian Cox
Genentech Research and Early Development, Genentech, Inc.
Alsu Missarova
Genentech Research and Early Development, Genentech, Inc.
Alexander Arlantico
Genentech Research and Early Development, Genentech, Inc.
Ben Hall
Genentech Research and Early Development, Genentech, Inc.
Ruoyu Zhang
David Kim
Genentech Research and Early Development, Genentech, Inc.
Anthony Altieri
Department of Immunology, University of Toronto
Shakir Hasan
Department of Immunology, University of Toronto
Afshin Namdar
Department of Immunology, University of Toronto
Tina Chen
Hospital for Sick Children Research Institute
Shaheed W. Hakim
St. Joseph’s Health Centre, Unity Health Toronto
Cynthia Guidos
Hospital for Sick Children Research Institute
Hans D. Brightbill
Genentech Research and Early Development, Genentech, Inc.
Tony Kuo
Roche Informatics, F. Hoffmann-La Roche Ltd.
Graham Heimberg
Genentech Research and Early Development, Genentech, Inc.
Héctor Corrada Bravo
Genentech Research and Early Development, Genentech, Inc.
Rojo A. Ratsimandresy
Genentech Research and Early Development, Genentech, Inc.
Salil Uttarwar
Genentech Research and Early Development, Genentech, Inc.
Grace Teng
Genentech Research and Early Development, Genentech, Inc.
Omar Salem
Genentech Research and Early Development, Genentech, Inc.
Mehrdad Arjomandi
Department of Medicine, University of California San Francisco
Mark S. Wilson
Genentech Research and Early Development, Genentech, Inc.
Spyros Darmanis
James Ziai
Genentech Research and Early Development, Genentech, Inc.
Alexis Scherl
Pathology, Genentech
Zora Modrusan
Paul J. Wolters
Department of Medicine, University of California San Francisco
Matthew B. Buechler
University of Toronto, Department of Immunology, Toronto, ON, Canada.
Jason A. Vander Heiden
Genentech Research and Early Development, Genentech, Inc.
Shannon J. Turley
Genentech Research and Early Development, Genentech, Inc.