Abstract 4140393: Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts in vivo and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. In vivo , we deleted the IL-1 receptor on fibroblasts, the IL-1 ligand in CCR2 monocytes and macrophages, and inhibited IL-1 signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1 and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.

Authors

Institutions

Publication Details

Journal
Circulation
Published
2024-11-12
DOI
https://doi.org/10.1161/circ.150.suppl_1.4140393
Citations
1
Primary Topic
Cardiac Fibrosis and Remodeling
Type
article
Field-Weighted Citation Impact
0.40
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Abstract 4140393: Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

Simon Jackson, Junedh Amrute, Kory J. Lavine, Sally Yu Shi et al.
1 citations
Circulation
Cardiac Fibrosis and Remodeling
0.40
article

Abstract 4140393: Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

Simon Jackson, Junedh Amrute, Kory J. Lavine, Sally Yu Shi, Hannah Luehmann, Farid F. Kadyrov, Tracy Yamawaki, Andrea Bredemeyer, Vinay Penna, Rafael Kramann, Rajiu Venkatesan, Sikander Hayat, Nadia Rosenthal, Chi-Ming Li, Benjamin J. Kopecky, Attila D Kovács, Daniel Kreisel, Candice N. Baker, Yuriko Terada, Brandon Ason, Nathan O. Stitziel, Andrew L. Koenig, In‐Hyuk Jung, Angela Fu, Pan Ma, Steven Yang, Christoph Kuppe, Milena B. Furtado, Gyu Seong Heo, Cameran Jones, Alekhya Parvathaneni, Yongjian Liu, Xin Luo, Paul C. Lee, Xue Zeng, Tore Blekwehl
article en
1 citations

Abstract

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts in vivo and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. In vivo , we deleted the IL-1 receptor on fibroblasts, the IL-1 ligand in CCR2 monocytes and macrophages, and inhibited IL-1 signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1 and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.

CirculationVol. 150(Suppl_1)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US), Amgen (United States) (US), Washington University in St. Louis (US), Jackson Laboratory (US), RWTH Aachen University (DE), University of Colorado Denver (US)
Good health and well-being
Openalex Percentile: Top 30%
Cardiac Fibrosis and Remodeling
0.40
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.