Inflammation and fibrosis are intertwined mechanisms fundamentally involved in heart failure. Detailed deciphering gene expression perturbations and cell–cell interactions of leukocytes and non-myocytes is required to understand cell-type-specific pathology in the failing human myocardium. To this end, we performed single-cell RNA sequencing and single T cell receptor sequencing of 200,615 cells in both human dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts. We sampled both lesion and mild-lesion tissues from each heart to sequentially capture cellular and molecular alterations to different extents of cardiac fibrosis. By which, left (lesion) and right ventricle (mild-lesion) for DCM hearts were harvest while infarcted (lesion) and non-infarcted area (mild-lesion) were dissected from ICM hearts. A novel transcription factor AEBP1 was identified as a crucial cardiac fibrosis regulator in ACTA2⁺ myofibroblasts. Within fibrotic myocardium, an infiltration of a considerable number of leukocytes was witnessed, especially cytotoxic and exhausted CD8⁺ T cells and pro-inflammatory CD4⁺ T cells. Furthermore, a subset of tissue-resident macrophage, CXCL8^hiCCR2⁺HLA-DR^hi macrophage was particularly identified in severely fibrotic area, which interacted with activated endothelial cell via DARC, that potentially facilitate leukocyte recruitment and infiltration in human heart failure.

炎症和纤维化是从根本上与心力衰竭相关的相互交织的机制。需要详细解读白细胞和非心肌细胞的基因表达扰动和细胞间相互作用，以了解衰竭人类心肌中细胞类型特异性的病理学。为此，我们对人类扩张型心肌病 (DCM) 和缺血性心肌病 (ICM) 心脏中的 200,615 个细胞进行了单细胞 RNA 测序和单 T 细胞受体测序。我们对每颗心脏的病变组织和轻度病变组织进行了采样，以依次捕获不同程度的心脏纤维化的细胞和分子变化。由此，采集 DCM 心脏的左（病变）和右心室（轻度病变），同时从 ICM 心脏解剖梗塞（病变）和非梗塞区域（轻度病变）。一种新的转录因子AEBP1被确定为ACTA2 ⁺肌成纤维细胞中的关键心脏纤维化调节剂。在纤维化心肌内，可见大量白细胞浸润，尤其是细胞毒性和耗竭的 CD8 ⁺ T 细胞和促炎 CD4 ⁺ T 细胞。此外，组织驻留巨噬细胞的一个子集，CXCL8 ^hi CCR2 ⁺ HLA-DR ^hi巨噬细胞在严重纤维化区域中被特别鉴定，其通过DARC与活化的内皮细胞相互作用，这可能促进白细胞募集和在人类心力衰竭中的浸润。