通过线粒体共享和结构重塑对衰老的卵巢微环境进行重编程。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.119957
Chia-Jung Li, Li-Te Lin, Pei-Hsuan Lin, Jim Jinn-Chyuan Sheu, Zhi-Hong Wen, Kuan-Hao Tsui
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引用次数: 0

摘要

理由:卵巢颗粒细胞(GCs)和卵丘细胞(CCs)的线粒体功能障碍是生殖衰老的一个明显特征,导致卵母细胞质量受损和生育能力下降。本研究探讨增强细胞骨架动力学或促进细胞间结构接触是否能恢复线粒体功能并减缓卵巢衰老。方法:利用共培养系统、活细胞成像和线粒体标记对人卵巢体细胞进行线粒体交换评估。使用FTY720实现细胞骨架调节,并通过软3D细胞外基质(ECM)支架增强细胞间的接触。通过ATP测定、线粒体膜电位、海马生物能量谱和转录组学分析来评估功能结果。FTY720对老年小鼠进行了体内验证。结果:颗粒细胞和积云细胞通过隧道纳米管(TNTs)交换线粒体,这一过程随着年龄的增长而显著减少。线粒体转移是接触依赖性的,不受旁分泌信号的介导。FTY720增强了TNT的形成和线粒体递送,恢复了衰老细胞的ATP水平、膜电位和氧化磷酸化。3D ECM培养促进球体形成,激活YAP信号,改善线粒体功能,无需药物。在老年小鼠中,FTY720处理增加了卵泡数量,改善了卵母细胞线粒体质量,提高了血清AMH水平。结论:这些发现表明,体细胞接触是衰老卵巢线粒体互补的必要条件。通过细胞骨架或微环境重塑促进细胞间连通性,内源性线粒体共享可以被重新激活以恢复生物能量功能。这种方法提供了一种新的再生策略来对抗生殖衰老。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reprogramming the aging ovarian microenvironment via mitochondrial sharing and structural remodeling.

Rationale: Mitochondrial dysfunction in ovarian granulosa cells (GCs) and cumulus cells (CCs) is a defining feature of reproductive aging, contributing to impaired oocyte quality and reduced fertility. This study investigates whether enhancing cytoskeletal dynamics or promoting structural contact between cells can restore mitochondrial function and mitigate ovarian aging. Methods: Mitochondrial exchange was assessed using co-culture systems, live-cell imaging, and mitochondrial labeling in human ovarian somatic cells. Cytoskeletal modulation was achieved using FTY720, and cell-cell contact was enhanced through soft 3D extracellular matrix (ECM) scaffolds. Functional outcomes were evaluated through ATP assays, mitochondrial membrane potential, Seahorse bioenergetics profiling, and transcriptomic analysis. In vivo validation was conducted in aged mice treated with FTY720. Results: Granulosa and cumulus cells exchanged mitochondria via tunneling nanotubes (TNTs), a process significantly reduced with age. Mitochondrial transfer was contact-dependent and not mediated by paracrine signaling. FTY720 enhanced TNT formation and mitochondrial delivery, restoring ATP levels, membrane potential, and oxidative phosphorylation in aged cells. 3D ECM culture promoted spheroid formation, activated YAP signaling, and improved mitochondrial function without pharmacological agents. In aged mice, FTY720 treatment increased follicle numbers, improved oocyte mitochondrial quality, and elevated serum AMH levels. Conclusions: These findings demonstrate that somatic cell contact is essential for mitochondrial complementation in aging ovaries. By promoting intercellular connectivity through cytoskeletal or microenvironmental remodeling, endogenous mitochondrial sharing can be reactivated to restore bioenergetic function. This approach offers a novel regenerative strategy to counteract reproductive aging.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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