Pan-valvular heart diseases single-cell transcriptional atlas reveals phenotypically distinct myeloid cell subtypes
Z Zou, Q Yang, Z Zhang, H Shi, S Zheng, X Wang, Z Luo, J Song, S Liu, Y Yang, S ShuAbstract
Background
: Pan-valvular heart diseases (VHDs) are common and their prevalence are rapidly increasing worldwide. However, effective medical therapies are insufficient and treatment was limited to the surgical techniques of valve repair or replacement in VHDs. Myeloid cells are increasingly valued in VHDs, which may be the key regulators in VHDs progression. Exploring the innate immune mechanism of pan-VHDs at the single cell level may be useful to identify novel immunotherapy targets.
Purpose
: To dissect the similarity and distinction of myeloid cells fundamental properties across different VHDs.
Methods
: Performing a pan-VHDs analysis of single myeloid cells from 87 patients across 12 sample types, including 15 calcified aortic valve disease (AV_CAVD), 3 aortic valve regurgitation (AV_AVR), 14 rheumatic heart disease (5 AV_RHD, 9 MV_RHD), 6 infective endocarditis (3 AV_IE, 3 MV_IE), 9 functional valve regurgitation (4 MV_FVR, 5 TV_FVR), and 40 normal tissues without diseases (21 AV_ND, 7 MV_ND, 6 TV_ND, 6 PV_ND). Bioinformatics was used to identify the myeloid lineages, describe the myeloid subsets functions, and investigate cellular developmental trajectories and interactions. Homogeneity and heterogeneity among the 12 types of cardiac valves at the myeloid cellular level were also summarized. Multi-color immunohistochemistry staining was performed to validate the critical findings of single-cell RNA sequencing.
Results
: Six major myeloid lineages were identified among 87,278 myeloid cells from 87 patients across 12 valvular sample types, including monocytes, macrophages, neutrophils, mast cells, conventional dendritic cells, and plasmacytoid dendritic cells, and macrophages representing the most abundant and transcriptionally heterogeneous population. Notably, neutrophils were almost exclusively enriched in IE. Further dissection of the monocyte/macrophage revealed 10 distinct subsets. Among these, PDE4C⁺ and MS4A4E⁺ macrophages were significantly enriched in CAVD and exhibited gene signatures associated with macrophage-to-myofibroblast transition, TGF-β and PI3K/Akt signaling. CCL8⁺ macrophages were preferentially enriched in RHD and displayed features of immune regulation and response to TGF-β. In particular, we identified that APOC1⁺ macrophages were broadly enriched across multiple VHD types and exhibited high differentiation potential. Additionally, we demonstrated that APOC1⁺ macrophages with high CXCL5 expression showed enhanced immune modulation in pan-VHDs, and strongly interact with other myeloid cells, potentially promoting immune microenvironment reprogramming and valvular tissue remodeling.
Conclusions
: The current study offers a comprehensive landscape and deep insight into myeloid subsets and microenvironmental reprogramming throughout pan-VHDs, and suggests future targeted immunotherapies.Identification of myeloid cell subsetsOverview of the current study