间充质干细胞的衰老与抗衰策略研究进展

doi:10.3877/cma.j.issn.2095-1221.2026.02.007

间充质干细胞（MSCs）因其强大的自我更新能力、低免疫原性以及多向分化潜能，在再生医学领域展现出广阔的应用前景。然而，在体外扩增过程中，由于培养环境与体内生理状态存在差异，MSCs易发生复制性衰老，表现为增殖能力减缓、分化潜能降低及功能减弱，从而极大限制其临床转化与应用。近年来，国内外研究者致力于探索多种延缓MSCs衰老的策略，并已在基因修饰、培养体系优化及生物材料应用等方面取得进展。本文系统综述该领域的最新研究进展，旨在为提高MSCs的体外培养质量、维持其功能特性提供理论依据，进一步拓展其在组织工程与细胞治疗中的临床应用。

关键词: 间充质干细胞, 衰老, 预处理

Mesenchymal stem cells (MSCs) have shown broad application prospects in the field of regenerative medicine due to their strong self-renewal ability, low immunogenicity and multi-directional differentiation potential. However, during the in vitro expansion, due to the differences between the culture environment and the physiological state in vivo, MSCs are prone to replicative senescence, which is manifested as slowed proliferation ability, reduced differentiation capacity and weakened function, thereby limiting their clinical transformation and application. Recently, significant efforts have been made to develop effective strategies to delay MSC aging and have made significant progress in gene modification, optimization of culture systems, and application of biomaterials. This review highlights recent advances in approaches to delay senescence in MSCs, aiming to provide a theoretical basis for improving the quality of in vitro culture of MSCs and maintaining their functional characteristics and broaden the scope of MSC applications in tissue engineering and cell-based therapies.

Key words: Mesenchymal stem cells, Senescence, Preconditioning

图1 MSCs衰老相关机制及处理策略（Biorender绘制）注：ROS为活性氧；DNA为脱氧核糖核酸；Wnt为无翼相关整合位点；TGF-β为转化生长因子β；PI3K为磷脂酰肌醇3-激酶；AKT为蛋白激酶B；mTOR为雷帕霉素靶蛋白；MSCs为间充质干细胞

表1 抗MSCs衰老策略总结

抗衰老策略	实施方法	抗衰机制	优点	缺点
物质预处理	添加特定物质，包括：小分子化合物：CHIR 99021^[44]、SB431542^[45]、达沙替尼^[46]、氯化钴^[50]；天然提取物：白藜芦醇^[51]；生长因子：VEGF、FGF^[48]、IGF^[49]等	作用于SIRT1信号通路，增强细胞应激抗性；作用于HIF-1α信号通路，改变能量代谢方式；作用于热休克蛋白改善线粒体功能等	操作简便、成本可控、安全性高；适合在细胞制备车间中进行大规模生产；加入已知物质，药代动力学和毒理学资料完善	难以从根本上解决衰老问题；作用靶点和分子机制难以完全阐明；可能存在未知的体内相互作用；细胞批次间差异
基因修饰	直接干预MSCs遗传物质，从基因层面调控生物学行为，包括：基因过表达：BDNF^[56]、TCAB1^[57]、CPT1A^[58]、SOX5^[61]；基因敲低敲除：沉默CircSERPINE2^[64]；多重基因编辑：抗衰型人间充质祖细胞技术^[65]；构建永生细胞系^[21]等	激活SIRT1通路；过表达HIF-1α；抑制ALDH2等	从根本上靶向性解决细胞衰老问题；效果显著且持久；可以对细胞多个基因同时修饰，赋予细胞多重特性	耗时长、成本高、技术难；潜在的致癌和突变风险；仍需长期安全性评估
物理方法	施加物理因素改善MSCs微环境或者直接刺激细胞，包括：材料学工程：PVA-GA超分子热可逆水凝胶^[67]；三维培养：基于胶原蛋白制备的微球多孔载体^[76]；低氧预处理^[71,72]；电磁波冲击波^[73,74]等	模拟重塑细胞支撑骨架；模拟体内微环境；重编程能量代谢维持稳态；改善细胞间通讯；增强细胞基质相互作用等	可以规避化学物质残留和基因突变风险；物理刺激参数可控、可精准量化	对生产设备依赖性强；培养材料制定成本高昂；机制探究不够深入；抗细胞衰老效果不持久

表1 抗MSCs衰老策略总结

抗衰老策略	实施方法	抗衰机制	优点	缺点
物质预处理	添加特定物质，包括：小分子化合物：CHIR 99021^[44]、SB431542^[45]、达沙替尼^[46]、氯化钴^[50]；天然提取物：白藜芦醇^[51]；生长因子：VEGF、FGF^[48]、IGF^[49]等	作用于SIRT1信号通路，增强细胞应激抗性；作用于HIF-1α信号通路，改变能量代谢方式；作用于热休克蛋白改善线粒体功能等	操作简便、成本可控、安全性高；适合在细胞制备车间中进行大规模生产；加入已知物质，药代动力学和毒理学资料完善	难以从根本上解决衰老问题；作用靶点和分子机制难以完全阐明；可能存在未知的体内相互作用；细胞批次间差异
基因修饰	直接干预MSCs遗传物质，从基因层面调控生物学行为，包括：基因过表达：BDNF^[56]、TCAB1^[57]、CPT1A^[58]、SOX5^[61]；基因敲低敲除：沉默CircSERPINE2^[64]；多重基因编辑：抗衰型人间充质祖细胞技术^[65]；构建永生细胞系^[21]等	激活SIRT1通路；过表达HIF-1α；抑制ALDH2等	从根本上靶向性解决细胞衰老问题；效果显著且持久；可以对细胞多个基因同时修饰，赋予细胞多重特性	耗时长、成本高、技术难；潜在的致癌和突变风险；仍需长期安全性评估
物理方法	施加物理因素改善MSCs微环境或者直接刺激细胞，包括：材料学工程：PVA-GA超分子热可逆水凝胶^[67]；三维培养：基于胶原蛋白制备的微球多孔载体^[76]；低氧预处理^[71,72]；电磁波冲击波^[73,74]等	模拟重塑细胞支撑骨架；模拟体内微环境；重编程能量代谢维持稳态；改善细胞间通讯；增强细胞基质相互作用等	可以规避化学物质残留和基因突变风险；物理刺激参数可控、可精准量化	对生产设备依赖性强；培养材料制定成本高昂；机制探究不够深入；抗细胞衰老效果不持久

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Advances in aging and anti-aging strategies of mesenchymal stem cells

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Advances in aging and anti-aging strategies of mesenchymal stem cells