Ameliorating replicative senescence of human bone marrow stromal cells by PSMB5 overexpression
Ameliorating replicative senescence of human bone marrow stromal cells by PSMB5 overexpression
复制标题
通过 PSMB5 过表达改善人骨髓基质细胞的复制衰老
DOI：
10.1016/j.bbrc.2013.12.113
复制
发表时间：
2014-01-24
影响因子：
3.1
通讯作者：
Yang, Wu-Lin
中科院分区：
文献类型：
--
作者：
Lu, Li;Song, Hui-Fang;Yang, Wu-Lin
多能人骨髓基质细胞（hBMSC）有可能成为再生医学中细胞疗法的来源。然而，体外扩增不可避免地伴随着细胞衰老，其特征是增殖受到抑制和多能性受损。我们之前已经证明，这种衰老过程与 20S 蛋白酶体活性降低密切相关，限速催化 β 亚基的下调尤其明显。在本研究中，我们证实蛋白酶体活性直接导致hBMSCs的衰老，而β5亚基（PSMB5）的过度表达可以逆转这种衰老。敲除 PSMB5 会导致早期 hBMSC 中蛋白酶体活性降低，同时细胞增殖减少，这与晚期细胞中观察到的衰老表型相似。相比之下，在晚期细胞中过表达 PSMB5 可能通过上调 Cyclin D1/CDK4 复合物有效恢复 20S 蛋白酶体的正常活性并促进细胞生长。此外，PSMB5 可以增强细胞对氧化应激的抵抗力，将衰老的 hBMSC 暴露于过氧化氢后细胞存活率增加就证明了这一点。此外，PSMB5 过表达通过促进体外和体内的神经分化来保留晚期 hBMSC 的多能性。总的来说，我们的工作揭示了 PSMB5 在 20S 蛋白酶体介导的复制衰老保护中的关键作用，指出了通过操纵 PSMB5 的表达来维持培养扩增的 hBMSC 完整性的可能策略。 (C) 2013 Elsevier Inc. 保留所有权利。
Multipotent human bone marrow stromal cells (hBMSCs) potentially serve as a source for cell-based therapy in regenerative medicine. However, in vitro expansion was inescapably accompanied with cell senescence, characterized by inhibited proliferation and compromised pluripotency. We have previously demonstrated that this aging process is closely associated with reduced 20S proteasomal activity, with down-regulation of rate-limiting catalytic beta-subunits particularly evident. In the present study, we confirmed that proteasomal activity directly contributes to senescence of hBMSCs, which could be reversed by overexpression of the beta 5-subunit (PSMB5). Knocking down PSMB5 led to decreased proteasomal activity concurrent with reduced cell proliferation in early-stage hBMSCs, which is similar to the senescent phenotype observed in late-stage cells. In contrast, overexpressing PSMB5 in late-stage cells efficiently restored the normal activity of 20S proteasomes and promoted cell growth, possibly via upregulating the Cyclin D1/CDK4 complex. Additionally, PSMB5 could enhance cell resistance to oxidative stress, as evidenced by the increased cell survival upon exposing senescent hBMSCs to hydrogen peroxide. Furthermore, PSMB5 overexpression retained the pluripotency of late-stage hBMSCs by facilitating their neural differentiation both in vitro and in vivo. Collectively, our work reveals a critical role of PSMB5 in 20S proteasome-mediated protection against replicative senescence, pointing to a possible strategy for maintaining the integrity of culture-expanded hBMSCs by manipulating the expression of PSMB5. (C) 2013 Elsevier Inc. All rights reserved.