M1 macrophage-derived extracellular vesicle containing tsRNA-5006c promotes osteogenic differentiation of aortic valve interstitial cells through regulating mitophagy

PeerJ

article

Hao Xia¹  Mingjian Gao¹  Jun Chen²  Guanshen Huang¹  Xiuting Xiang¹  Yuyan Wang¹  Zhaohui Huang¹  Yongchun Li³  Shuang Su¹  Zewei Zhao¹  Qingchun Zeng²  Yunjun Ruan¹ 

[1] Department of Geriatrics, Nanfang Hospital, Southern Medical University;Department of Cardiology, Southern University of Science and Technology Hospital;Department of traditional Chinese Medicine, Nanfang Hospital, Southern Medical University

关键词: Osteogenic differentiation;    tRNA-derived small RNA;    Extracellular vesicles;    Macrophage M1 polarization;    Mitophagy;   

DOI  :  10.7717/peerj.14307

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

BackgroundOsteogenic differentiation of aortic valve interstitial cells (AVICs) plays a key role in the calcific aortic valve disease progression. Extracellular vesicles (EVs)-derived from M1-polarized macrophages (M1-EVs) orchestrated intercellular communication by delivering non-coding RNAs such as tRNA-derived small RNAs (tsRNAs) is crucial for cardiovascular disease. However, the role and mechanism of M1-EVs tsRNAs in osteogenic differentiation of AVICs remains largely unclear.MethodsM1-EVs and PBS treated-RAW 264.7 cell-derived EVs (NC-EVs) were incubated with AVICs and subjected to small RNA sequencing. Candidate tsRNA in M1-EVs was silenced to explore their effects on AVIC osteogenic differentiation and mitophagy.ResultsDiI-labeled M1-EVs were internalized by AVICs, resulting in significantly increased calcium nodule formation and expression of osteogenesis-related genes in AVICs, including RUNX2, BMP2, osteopontin, and SPP1, compared with NC-EVs. Small RNA sequencing revealed that 17 tsRNAs were significantly up-regulated such as tsRNA-5006c, while 28 tsRNAs were significantly down-regulated in M1-EVs compared with NC-EVs. Intriguingly, tsRNA-5006c-deleted M1-EVs treatment significantly reduced calcium nodule formation and expression of osteogenesis-related genes in AVICs relative to control group. Moreover, target genes of tsRNA-5006c were mainly involved in autophagy-related signaling pathways, such as MAPK, Ras, Wnt, and Hippo signaling pathway. Hallmarks of mitophagy activation in AVICs including mitophagosome formation, TMRM fluorescence, expression of LC3-II, BINP3, and PGC1α, were significantly elevated in the M1-EVs group compared with NC-EVs group, whereas M1-EVs tsRNA-5006c inhibitor led to a significant reduction in these indicators.ConclusionM1-EVs carried tsRNA-5006c regulates AVIC osteogenic differentiation from the perspective of mitophagy, and we provide a new target for the prevention and treatment of aortic valve calcification.

【 授权许可】

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