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

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          Abstract

          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.

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          Most cited references48

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          The biology, function, and biomedical applications of exosomes

          The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.
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            Is Open Access

            MAPK/JNK signalling: a potential autophagy regulation pathway

            Herein, MAPK/JNK signalling is proposed as a potential autophagy regulation pathway for the transcription-dependent or independent role.
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              M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages.

              M2-polarized, pro-tumoral tumor-associated macrophages (TAMs) express the interleukin-4 receptor (IL4R) at higher levels compared with M1-polarized, anti-tumoral macrophages. In this study, we harnessed M1 macrophage-derived exosomes engineered to foster M1 polarization and target IL4R for the inhibition of tumor growth by reprogramming TAMs into M1-like macrophages. M1 exosomes were transfected with NF-κB p50 siRNA and miR-511-3p to enhance M1 polarization and were surface-modified with IL4RPep-1, an IL4R-binding peptide, to target the IL4 receptor of TAMs (named IL4R-Exo(si/mi). IL4R-Exo(si/mi) were internalized and downregulated target gens in M2 macrophages and decreased M2 markers, while increasing M1 markers, more efficiently compared with untargeted and control peptide-labeled exosomes and exosomes from non-immune, normal cells. Whole-body fluorescence imaging showed that IL4R-Exo(si/mi) homed to tumors at higher levels compared with the liver, unlike untargeted and control peptide-labeled exosomes. Systemic administration of IL4R-Exo(si/mi) inhibited tumor growth, downregulated target genes, and decreased the levels of M2 cytokines and immune-suppressive cells, while increasing the levels of M1 cytokines and immune-stimulatory cells, more efficiently than untargeted and control peptide-labeled exosomes. These results suggest that IL4R-Exo(si/mi) inhibits tumor growth by reprogramming TAMs into M1-like macrophages and increasing anti-tumor immunity, thus representing a novel cancer immunotherapy.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                peerj
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                2 December 2022
                2022
                : 10
                : e14307
                Affiliations
                [1 ]Department of Geriatrics, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
                [2 ]Department of Cardiology, Southern University of Science and Technology Hospital , Shenzhen, Guangdong, China
                [3 ]Department of traditional Chinese Medicine, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
                Article
                14307
                10.7717/peerj.14307
                9744173
                36518291
                5b1ae3f3-5da6-456b-a184-7fcdb90592a4
                ©2022 Xia et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 18 August 2022
                : 5 October 2022
                Funding
                Funded by: The Science and Technology Planning Project of Guangzhou City
                Award ID: 201903010090
                This work was supported by the Science and Technology Planning Project of Guangzhou City [201903010090]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Molecular Biology
                Cardiology

                osteogenic differentiation,trna-derived small rna,extracellular vesicles,macrophage m1 polarization,mitophagy

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