美国华盛顿大学医学院Kory J. Lavine团队近期取得重要工作进展，他们研究提出能以心力衰竭中的免疫-成纤维细胞通讯为靶点来治疗心脏纤维化疾病。相关研究成果2024年10月23日在线发表于《自然》杂志上。

据介绍，炎症和组织纤维化共存，并与器官功能障碍密切相关。然而，在人类心脏病中驱动免疫-成纤维细胞通讯的分子机制尚未得到探索，目前还没有批准的直接针对心脏纤维化的治疗方法。

研究人员在45名健康供体、急性梗死和慢性衰竭的人类心脏中进行了多组单细胞基因表达、表位作图和染色质可及性分析。研究人员发现了一种与疾病相关的成纤维细胞轨迹，它分化为不同的群体，让人联想到肌成纤维细胞和基质纤维细胞，后者表达成纤维细胞激活蛋白（FAP）和骨膜炎蛋白（POSTN）。FAP⁺成纤维细胞在体内的遗传谱系追踪表明，它们对POSTN谱系有贡献，但对肌成纤维细胞谱系没有贡献。

研究人员评估了实验系统对心脏成纤维细胞模型的适用性，并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类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，白细胞介素-1β（IL-1β）信号介导的C-C趋化因子受体2型（CCR2）巨噬细胞和成纤维细胞之间的相互作用促使FAP/POSTN成纤维细胞在空间限定的生态位内出现。

在体内，研究人员删除了成纤维细胞上的IL-1受体和CCR2⁺单核细胞和巨噬细胞中的IL-1β配体，并使用单克隆抗体抑制IL-1β信号传导，结果显示FAP/POSTN成纤维细胞减少，心肌纤维化减轻，心功能改善。

总之，这一研究强调了靶向炎症治疗组织纤维化和保护器官功能的更广泛的治疗潜力。

附：英文原文

Title: Targeting immune–fibroblast cell communication in heart failure

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

Issue&Volume: 2024-10-23

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.

DOI: 10.1038/s41586-024-08008-5

Source: https://www.nature.com/articles/s41586-024-08008-5