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

Xia, Hao1; Gao, Mingjian1; Chen, Jun2; Huang, Guanshen1; Xiang, Xiuting1; Wang, Yuyan1; Huang, Zhaohui1; Li, Yongchun3; Su, Shuang1; Zhao, Zewei1; Zeng, Qingchun2; Ruan, Yunjun1

2022-12-02

10.7717/peerj.14307

PeerJ   Impact Factor & Quartile

2167-8359

2167-8359

Background. Osteogenic 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. Methods. M1-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. Results. DiI-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. Conclusion. M1-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.

Extracellular vesicles Macrophage M1 polarization Mitophagy Osteogenic differentiation tRNA-derived small RNA

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Science and Technology Planning Project of Fuzhou[201903010090];

Science & Technology - Other Topics

Multidisciplinary Sciences

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PEERJ INC

2-s2.0-85143408963

Scopus

1.Southern Med Univ, Nanfang Hosp, Dept Geriatr, Guangzhou, Guangdong, Peoples R China
2.Southern Univ Sci & Technol Hosp, Dept Cardiol, Shenzhen, Guangdong, Peoples R China
3.Southern Med Univ, Nanfang Hosp, Dept Tradit Chinese Med, Guangzhou, Guangdong, Peoples R China

Xia, Hao,Gao, Mingjian,Chen, Jun,et al. M1 macrophage-derived extracellular vesicle containing tsRNA-5006c promotes osteogenic differentiation of aortic valve interstitial cells through regulating mitophagy[J]. PeerJ,2022,10.

Xia, Hao.,Gao, Mingjian.,Chen, Jun.,Huang, Guanshen.,Xiang, Xiuting.,...&Ruan, Yunjun.(2022).M1 macrophage-derived extracellular vesicle containing tsRNA-5006c promotes osteogenic differentiation of aortic valve interstitial cells through regulating mitophagy.PeerJ,10.

Xia, Hao,et al."M1 macrophage-derived extracellular vesicle containing tsRNA-5006c promotes osteogenic differentiation of aortic valve interstitial cells through regulating mitophagy".PeerJ 10(2022).