Targeting immune–fibroblast cell communication in heart failure

Affiliations

• Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
• Amgen Discovery Research, Amgen Inc., South San Francisco, CA, USA
• Institute of Experimental Medicine and Systems Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
• Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA
• Department of Nephrology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
• Jackson Laboratory, Bar Harbor, ME, USA
• Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
• Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
• Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA
• McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
• Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands
• Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, USA

PMID:  10.1038/s41586-024-08008-5  DOI: 

Abstract

Infammation and tissue fbrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune–fbroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fbrosis. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identifed a disease-associated fbroblast trajectory that diverged into distinct populations reminiscent of myofbroblasts and matrifbrocytes, the latter expressing fbroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fbroblasts in vivo showed that they contribute to the POSTN lineage but not the myofbroblast lineage. We assessed the applicability of experimental systems to model cardiac fbroblasts and demonstrated that three diferent in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fbroblasts 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 fbroblasts mediated by interleukin-1β (IL-1β) signalling drove the emergence of FAP/POSTN fbroblasts within spatially defned niches. In vivo, we deleted the IL-1 receptor on fbroblasts and the IL-1β ligand in CCR2+ monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fbroblasts, diminished myocardial fbrosis and improved cardiac function. These fndings highlight the broader therapeutic potential of targeting infammation to treat tissue fbrosis and preserve organ function.

炎症和组织纤维化共存，并与器官功能障碍有因果关系。然而，在人类心脏疾病中驱动免疫细胞与成纤维细胞之间通信的分子机制仍未被探索，目前尚无针对心脏纤维化的批准治疗方法。我们在45个健康供体、急性心肌梗死和慢性心衰的人的心脏中进行了多组学单细胞基因表达、表位映射和染色质可及性分析。我们识别出一种与疾病相关的成纤维细胞轨迹，该轨迹分化为不同的群体，类似于肌成纤维细胞和母成纤维细胞，后者表达成纤维细胞活化蛋白（FAP）和骨膜素（POSTN）。FAP+成纤维细胞在体内的遗传谱系追踪显示，它们贡献于POSTN谱系，而非肌成纤维细胞谱系。我们评估了实验系统在建模心脏成纤维细胞中的适用性，证明三种不同的体内小鼠心脏损伤模型在重现人类疾病表型方面优于培养的人心脏和皮肤成纤维细胞。配体-受体分析和空间转录组学预测，C-C趋化因子受体2型（CCR2）巨噬细胞与成纤维细胞之间的相互作用由白介素-1β（IL-1β）信号介导，驱动FAP/POSTN成纤维细胞在空间特定生态位内的出现。在体内，我们删除了成纤维细胞上的IL-1受体和CCR2+单核细胞及巨噬细胞中的IL-1β配体，并使用单克隆抗体抑制IL-1β信号，结果显示FAP/POSTN成纤维细胞减少、心肌纤维化减轻、心脏功能改善。这些发现强调了靶向炎症治疗组织纤维化和维持器官功能的广泛治疗潜力。

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