scRNA‐seq reveals NAMPT‐mediated macrophage polarization shapes smooth muscle cell plasticity in pulmonary arterial hypertension

Autor: Zuoshi Wen, Liujun Jiang, Fangcong Yu, Xiaodong Xu, Mengjia Chen, Chenxi Li, Zhangquan Ying, Jianing Xue, Pengwei Zhu, Mairedan Muhetarijiang, Qingbo Xu, Zhoubin Li, Ting Chen
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Interdisciplinary Medicine, Vol 2, Iss 4, Pp n/a-n/a (2024)
Druh dokumentu: article
ISSN: 2832-6245
DOI: 10.1002/INMD.20240016
Popis: Abstract Phenotypic switching of smooth muscle cells (SMC) is a crucial process in the pathogenesis of pulmonary arterial hypertension (PAH). However, the underlying mechanism is unclear. Here, we performed single‐cell RNA sequencing on pulmonary arteries obtained from lung transplantation to explore the cellular heterogeneity and gene expression profile of the main cell types. We identified three distinct SMC phenotypes, namely contractile, fibroblast‐like, and chondroid‐like, and observed an enhanced transition from contractile to fibroblast‐like phenotype in PAH by pseudo‐time analysis and in vitro. We also revealed a classically activated (M1) polarization of macrophages and an increased pro‐inflammatory macrophage‐SMC crosstalk in PAH via intercellular communication. Notably, Nicotinamide phosphoribosyltransferase (NAMPT) emerges as a key player in macrophage polarization. The macrophages overexpress Nampt in Sugen/hypoxia (Su/Hx) ‐induced PAH mice and significantly downregulate the pro‐inflammation secretion pattern with Nampt interference. In a cellular coculture system, Nampt knockdown in macrophages significantly inhibits the fibroblast‐like phenotypic switching of SMCs. Finally, we identified Ccl2/5 as a key cytokine for SMC phenotypic modulation. Collectively, these findings provide a cell atlas of normal human pulmonary arteries and demonstrate that NAMPT‐driven M1 macrophage polarization promotes the fibroblast‐like phenotypic switching of SMCs through CCR2/CCR5 cellular crosstalk in PAH.
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