tsRNA-12391-Modified Adipose Mesenchymal Stem Cell-Derived Exosomes Mitigate Cartilage Degeneration in Osteoarthritis by Enhancing Mitophagy

IF 3.2 3区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS
Jingsheng Shi, Guanglei Zhao, Siqun Wang, Yibing Wei, Jianguo Wu, Gangyong Huang, Jie Chen, Jun Xia
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Abstract

Osteoarthritis (OA) is a cartilage-degenerative joint disease. Mitophagy impacts articular cartilage damage. tRNA-derived small RNAs (tsRNAs) are one of the contents of adipose mesenchymal stem cell (AMSC)-derived exosomes (AMSC-exos) and are involved in disease progression. However, whether tsRNAs regulate mitophagy and whether tsRNA-modified AMSC-exos improve OA via mitophagy remain unclear. We performed small RNA sequencing to identify OA-related tsRNAs, which were then loaded into AMSC-exos, exploring the function and mechanisms related to mitophagy in vitro and in vivo. Overall, 53 differentially expressed tsRNAs (DEtsRNAs) were identified between OA and normal cartilage tissues, among which 42 DEtsRNAs, including tsRNA-12391, were downregulated in the OA group. Target genes of tsRNA-12391 mainly participated in mitophagy-related pathways such as Rap1 signaling pathway. Compared to the control group, tsRNA-12391 mimics significantly promoted mitophagy, as shown by the upregulated expression of PINK1 and LC3 and the co-localization of Mito-Tracker Green and PINK1. Furthermore, tsRNA-12391 mimics effectively enhanced chondrogenesis in chondrocytes, as demonstrated by the elevated expression of collagen II and ACAN. AMSC-exos with tsRNA-12391 overexpression also facilitated mitophagy and chondrogenesis in vitro and in vivo. Mechanistically, tsRNA-12391 bound to ATAD3A restricted ATAD31 from degrading PINK1, leading to PINK1 accumulation. ATAD31 overexpression reversed the effects of tsRNA-12391 mimics on mitophagy and chondrogenesis. AMSC-exos loaded with tsRNA-12391 promoted mitophagy and chondrogenesis by interacting with ATAD31; this may be a novel therapeutic strategy for OA.

tsrna -12391修饰的脂肪间充质干细胞衍生外泌体通过增强线粒体自噬减轻骨关节炎软骨变性
骨关节炎是一种软骨退行性关节疾病。线粒体自噬影响关节软骨损伤。trna衍生小rna (tsrna)是脂肪间充质干细胞(AMSC)衍生外泌体(AMSC-exos)的内容物之一,参与疾病进展。然而,tsrna是否调节线粒体自噬以及tsrna修饰的AMSC-exos是否通过线粒体自噬改善OA仍不清楚。我们通过小RNA测序鉴定oa相关的tsRNAs,然后将其加载到AMSC-exos中,在体外和体内探索与线粒体自噬相关的功能和机制。总的来说,在OA和正常软骨组织之间鉴定出53个差异表达的tssrnas (DEtsRNAs),其中包括tsRNA-12391在内的42个DEtsRNAs在OA组中下调。tsRNA-12391的靶基因主要参与有丝分裂相关的途径,如Rap1信号通路。与对照组相比,tsRNA-12391模拟物显著促进了线粒体自噬,表现为PINK1和LC3的表达上调以及Mito-Tracker Green和PINK1的共定位。此外,通过提高II型胶原和ACAN的表达,tsRNA-12391模拟物有效地促进了软骨细胞的软骨形成。tsRNA-12391过表达的AMSC-exos在体外和体内也促进了线粒体自噬和软骨形成。从机制上讲,与ATAD3A结合的tsRNA-12391限制了ATAD31降解PINK1,导致PINK1积累。ATAD31过表达逆转了tsRNA-12391模拟物对线粒体自噬和软骨形成的影响。装载tsRNA-12391的AMSC-exos通过与ATAD31相互作用促进线粒体自噬和软骨形成;这可能是OA的一种新的治疗策略。
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来源期刊
Biotechnology Journal
Biotechnology Journal Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
8.90
自引率
2.10%
发文量
123
审稿时长
1.5 months
期刊介绍: Biotechnology Journal (2019 Journal Citation Reports: 3.543) is fully comprehensive in its scope and publishes strictly peer-reviewed papers covering novel aspects and methods in all areas of biotechnology. Some issues are devoted to a special topic, providing the latest information on the most crucial areas of research and technological advances. In addition to these special issues, the journal welcomes unsolicited submissions for primary research articles, such as Research Articles, Rapid Communications and Biotech Methods. BTJ also welcomes proposals of Review Articles - please send in a brief outline of the article and the senior author''s CV to the editorial office. BTJ promotes a special emphasis on: Systems Biotechnology Synthetic Biology and Metabolic Engineering Nanobiotechnology and Biomaterials Tissue engineering, Regenerative Medicine and Stem cells Gene Editing, Gene therapy and Immunotherapy Omics technologies Industrial Biotechnology, Biopharmaceuticals and Biocatalysis Bioprocess engineering and Downstream processing Plant Biotechnology Biosafety, Biotech Ethics, Science Communication Methods and Advances.
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