Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells
Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells
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DOI：
10.1089/ars.2015.6359
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发表时间：
2016-03-20
影响因子：
6.6
通讯作者：
Kim, Seong Who
中科院分区：
文献类型：
--
作者：
Jin, Hye Jin;Lee, Hyang Ju;Kim, Seong Who
目的：细胞衰老及其分泌表型（衰老相关分泌表型[SASP]）在间充质基质细胞（MSCs）长期扩增后发生。需要进一步研究这种表型以提高基于MSC的细胞疗法的治疗效果。在这项研究中，我们表明，SASP和固有的衰老过程之间的正反馈在脐带血来源的间充质干细胞（UCB-MSCs）的衰老中起着至关重要的作用。结果如下：我们发现，单核细胞趋化蛋白-1（MCP-1）在UCB-MSCs扩增过程中作为SASP的主要成分分泌，并通过自分泌和旁分泌方式激活ROS-p38-MAPK-p53/p21信号级联，通过其同源受体趋化因子（c-c基序）受体2（CCR 2）加强衰老。激活的p53反过来增加了MCP-1的分泌，完成了一个前馈循环，触发了UCB-MSC的衰老程序。因此，UCB-MSC中CCR 2的敲低显著提高了它们在实验性过敏性哮喘模型中减轻气道炎症的治疗能力。此外，BMI 1（一种多梳蛋白）通过结合其调节元件来抑制MCP-1的表达。在UCB-MSC衰老过程中BMI 1水平的降低改变了MCP-1的表观遗传状态，包括H2 AK 119 Ub的丢失，并导致MCP-1的去抑制。创新：我们的研究结果提供了支持SASP作为UCB-MSC衰老的致病因素存在的第一个证据，并揭示了表观遗传调控和SASP之间迄今未被认识到的联系，以维持稳定的衰老表型。结论：UCB-MSC的衰老由MCP-1协调，MCP-1作为SASP的主要组分分泌，并由BMI 1表观遗传调节。抗氧化剂。氧化还原信号。24，471-485。
Aims: Cellular senescence and its secretory phenotype (senescence-associated secretory phenotype [SASP]) develop after long-term expansion of mesenchymal stromal cells (MSCs). Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC-based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood-derived MSCs (UCB-MSCs). Results: We found that monocyte chemoattractant protein-1 (MCP-1) was secreted as a dominant component of the SASP during expansion of UCB-MSCs and reinforced senescence via its cognate receptor chemokine (c-c motif) receptor 2 (CCR2) by activating the ROS-p38-MAPK-p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCB-MSCs. Accordingly, knockdown of CCR2 in UCB-MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP-1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB-MSC senescence altered the epigenetic status of MCP-1, including the loss of H2AK119Ub, and resulted in derepression of MCP-1. Innovation: Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB-MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype. Conclusion: Senescence of UCB-MSCs is orchestrated by MCP-1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1. Antioxid. Redox Signal. 24, 471-485.