Targeting immune–fibroblast cell communication in heart failure

Junedh M. Amrute, Xin Luo, Vinay Penna, Steven Yang, Tracy Yamawaki, Sikander Hayat, Andrea Bredemeyer, In-Hyuk Jung, Farid F. Kadyrov, Gyu Seong Heo, Rajiu Venkatesan, Sally Yu Shi, Alekhya Parvathaneni, Andrew L. Koenig, Christoph Kuppe, Candice Baker, Hannah Luehmann, Cameran Jones, Benjamin Kopecky, Xue Zeng, Tore Bleckwehl, Pan Ma, Paul Lee, Yuriko Terada, Angela Fu, Milena Furtado, Daniel Kreisel, Atilla Kovacs, Nathan O. Stitziel, Simon Jackson, Chi-Ming Li, Yongjian Liu, Nadia A. Rosenthal, Rafael Kramann, Brandon Ason and Kory J. Lavine ()
Additional contact information
Junedh M. Amrute: Washington University School of Medicine
Xin Luo: Amgen Inc.
Vinay Penna: Washington University School of Medicine
Steven Yang: Washington University School of Medicine
Tracy Yamawaki: Amgen Inc.
Sikander Hayat: RWTH Aachen University
Andrea Bredemeyer: Washington University School of Medicine
In-Hyuk Jung: Washington University School of Medicine
Farid F. Kadyrov: Washington University School of Medicine
Gyu Seong Heo: Washington University School of Medicine
Rajiu Venkatesan: Washington University School of Medicine
Sally Yu Shi: Amgen Inc.
Alekhya Parvathaneni: Washington University School of Medicine
Andrew L. Koenig: Washington University School of Medicine
Christoph Kuppe: RWTH Aachen University
Candice Baker: Jackson Laboratory
Hannah Luehmann: Washington University School of Medicine
Cameran Jones: Washington University School of Medicine
Benjamin Kopecky: Washington University School of Medicine
Xue Zeng: Amgen Inc.
Tore Bleckwehl: RWTH Aachen University
Pan Ma: Washington University School of Medicine
Paul Lee: Washington University School of Medicine
Yuriko Terada: Washington University School of Medicine
Angela Fu: Amgen Inc.
Milena Furtado: Amgen Inc.
Daniel Kreisel: Washington University School of Medicine
Atilla Kovacs: Washington University School of Medicine
Nathan O. Stitziel: Washington University School of Medicine
Simon Jackson: Amgen Inc.
Chi-Ming Li: Amgen Inc.
Yongjian Liu: Washington University School of Medicine
Nadia A. Rosenthal: Jackson Laboratory
Rafael Kramann: RWTH Aachen University
Brandon Ason: Amgen Inc.
Kory J. Lavine: Washington University School of Medicine

Nature, 2024, vol. 635, issue 8038, 423-433

Abstract: Abstract Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction1,2. However, the molecular mechanisms driving immune–fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis3,4. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with 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-1β (IL-1β) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1β ligand in CCR2+ monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08008-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:635:y:2024:i:8038:d:10.1038_s41586-024-08008-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08008-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().