Clearance of senescent cells with ABT-263 improves biological functions of synovial mesenchymal stem cells from osteoarthritis patients.
Clearance of senescent cells with ABT-263 improves biological functions of synovial mesenchymal stem cells from osteoarthritis patients.
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DOI：
10.1186/s13287-022-02901-4
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发表时间：
2022-06-03
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
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骨关节炎(OA)是一种以进行性软骨丧失为特征的年龄相关性关节疾病。滑膜间充质干细胞被认为是治疗骨性关节炎的细胞来源，然而，从骨性关节炎患者分离的滑膜间充质干细胞含有许多衰老细胞，这些细胞通过其衰老相关的分泌表型(SASP)和较差的软骨形成能力抑制软骨再生。本研究的目的是通过使用抗衰老药物ABT-263去除衰老细胞来改善骨性关节炎滑膜间充质干细胞的生物学功能。我们用ABT263处理5例骨性关节炎患者的滑膜间充质干细胞24小时，然后检测衰老相关β-半乳糖苷酶(SA-β-GAL)活性、B细胞淋巴瘤2(Bcl2)活性、细胞凋亡率、表面抗原表达、集落形成能力和多能性。ABT263可显著降低SA-β-GAL阳性细胞百分率和bcl2表达，并诱导早期和晚期细胞凋亡。在SA-β-GAL阳性细胞中有caspase-3的表达。经处理的MSCs形成了数量更多、直径更大的克隆。CD34在预处理细胞中的表达率降低。分化实验显示，ABT-263预处理增强了骨性关节炎滑膜间充质干细胞的成脂和成软骨能力。在软骨形成中，预处理细胞产生较多的糖胺聚糖和II型胶原，衰老标志物(p16和p21)和SASP因子(MMP-13和IL-6)的表达较低，而I型胶原的表达较少。用ABT-263对骨性关节炎患者滑膜间充质干细胞进行预处理，可以选择性地清除衰老细胞，从而改善细胞功能。这些发现表明，ABT-263可能为开发有效的基于细胞的OA治疗带来希望。网上版载有补充材料，可在10.1186/s13287-022-02901-4查阅。
Osteoarthritis (OA) is an age-related joint disease characterized by progressive cartilage loss. Synovial mesenchymal stem cells (MSCs) are anticipated as a cell source for OA treatment; however, synovial MSC preparations isolated from OA patients contain many senescent cells that inhibit cartilage regeneration through their senescence-associated secretory phenotype (SASP) and poor chondrogenic capacity. The aim of this study was to improve the biological function of OA synovial MSCs by removing senescent cells using the senolytic drug ABT-263. We pretreated synovial MSCs derived from 5 OA patients with ABT-263 for 24 h and then evaluated senescence-associated beta-galactosidase (SA-β-gal) activity, B cell lymphoma 2 (BCL-2) activity, apoptosis, surface antigen expression, colony formation ability, and multipotency. The ABT-263 pretreatment significantly decreased the percentage of SA-β-gal-positive cells and BCL-2 expression and induced early- and late-stage apoptosis. Cleaved caspase-3 was expressed in SA-β-gal-positive cells. The pretreated MSCs formed greater numbers of colonies with larger diameters. The expression rate of CD34 was decreased in the pretreated cells. Differentiation assays revealed that ABT-263 pretreatment enhanced the adipogenic and chondrogenic capabilities of OA synovial MSCs. In chondrogenesis, the pretreated cells produced greater amounts of glycosaminoglycan and type II collagen and showed lower expression of senescence markers (p16 and p21) and SASP factors (MMP-13 and IL-6) and smaller amounts of type I collagen. Pretreatment of synovial MSCs from OA patients with ABT-263 can improve the function of the cells by selectively eliminating senescent cells. These findings indicate that ABT-263 could hold promise for the development of effective cell-based OA therapy. The online version contains supplementary material available at 10.1186/s13287-022-02901-4.
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