Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
Mar Drugs. 2018 Apr 6;16(4):121. doi: 10.3390/md16040121.
Mesenchymal stem cells (MSCs) are a source for cell-based therapy. Although MSCs have the potential for tissue regeneration, their therapeutic efficacy is restricted by the uremic toxin, -cresol, in chronic kidney disease (CKD). To address this issue, we investigated the effect of fucoidan, a marine sulfated polysaccharide, on cellular senescence in MSCs. After -cresol exposure, MSC senescence was induced, as indicated by an increase in cell size and a decrease in proliferation capacity. Treatment of senescent MSCs with fucoidan significantly reversed this cellular senescence via regulation of SMP30 and p21, and increased proliferation through the regulation of cell cycle-associated proteins (CDK2, CDK4, cyclin D1, and cyclin E). These effects were dependent on FAK-Akt-TWIST signal transduction. In particular, fucoidan promoted the expression of cellular prion protein (PrP), which resulted in the maintenance of cell expansion capacity in -cresol-induced senescent MSCs. This protective effect of fucoidan on senescence-mediated inhibition of proliferation was dependent on the TWIST-PrP axis. In summary, this study shows that fucoidan protects against -cresol-induced cellular senescence in MSCs through activation of the FAK-Akt-TWIST pathway and suggests that fucoidan could be used in conjunction with functional MSC-based therapies in the treatment of CKD.
间充质干细胞 (MSCs) 是细胞治疗的来源。尽管 MSCs 具有组织再生的潜力，但它们的治疗效果受到慢性肾脏病 (CKD) 中尿毒症毒素 - 甲酚的限制。为了解决这个问题，我们研究了海洋硫酸多糖褐藻糖胶对 MSCs 细胞衰老的影响。在 - 甲酚暴露后，MSC 衰老被诱导，细胞大小增加和增殖能力下降表明这一点。褐藻糖胶处理衰老的 MSC 可通过调节 SMP30 和 p21 显著逆转这种细胞衰老，并通过调节细胞周期相关蛋白（CDK2、CDK4、cyclin D1 和 cyclin E）来增加增殖。这些作用依赖于 FAK-Akt-TWIST 信号转导。特别是，褐藻糖胶促进了细胞朊病毒蛋白 (PrP) 的表达，从而维持了 - 甲酚诱导的衰老 MSC 中的细胞扩增能力。褐藻糖胶对衰老介导的增殖抑制的这种保护作用依赖于 TWIST-PrP 轴。总之，这项研究表明，褐藻糖胶通过激活 FAK-Akt-TWIST 通路来防止 MSCs 中 - 甲酚诱导的细胞衰老，并表明褐藻糖胶可与基于功能 MSC 的疗法联合用于治疗 CKD。
