Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis

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 therapeutics to target fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 38 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. Pro-fibrotic fibroblasts were transcriptionally similar to cancer associated fibroblasts and expressed high levels of collagens and periostin (POSTN), thymocyte differentiation antigen 1 (THY-1), and endothelin receptor A (EDNRA) predicted to be driven by a RUNX1 gene regulatory network. 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-1β) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. This concept was validated through in silico transcription factor perturbation and in vivo inhibition of IL-1β signaling in fibroblasts where we observed reduced pro-fibrotic fibroblasts, preferential differentiation of fibroblasts towards myofibroblasts, and reduced cardiac fibrosis. Herein, we show a subset of macrophages signal to fibroblasts via IL-1β 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 restore organ function..

Medienart:	Preprint

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	ResearchSquare.com - (2023) vom: 26. Jan. Zur Gesamtaufnahme - year:2023

Sprache:	Englisch

Beteiligte Personen:

Lavine, Kory [VerfasserIn] Amrute, Junedh [VerfasserIn] Luo, Xin [VerfasserIn] Penna, Vinay [VerfasserIn] Bredemeyer, Andrea [VerfasserIn] Yamawaki, Tracy [VerfasserIn] Yang, Steven [VerfasserIn] Kadyrov, Farid [VerfasserIn] Heo, Gyu [VerfasserIn] Shi, Sally [VerfasserIn] Lee, Paul [VerfasserIn] Koenig, Andrew [VerfasserIn] Kuppe, Christoph [VerfasserIn] Jones, Cameran [VerfasserIn] Kopecky, Benjamin [VerfasserIn] Hayat, Sikander [VerfasserIn] Ma, Pan [VerfasserIn] Terada, Yuriko [VerfasserIn] Fu, Angela [VerfasserIn] Furtado, Milena [VerfasserIn] Kreisel, Daniel [VerfasserIn] Stitziel, Nathan [VerfasserIn] Li, Chi-Ming [VerfasserIn] Kramann, Rafael [VerfasserIn] Liu, Yongjian [VerfasserIn] Ason, Brandon [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.21203/rs.3.rs-2402606/v1

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	XRA038514125