Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells
Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells
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DOI：
10.1016/j.bone.2020.115252
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发表时间：
2020-04-01
期刊：
影响因子：
4.1
通讯作者：
Alfayez, Musaad
中科院分区：
文献类型：
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作者：
Ali, Dalia;Chen, Li;Alfayez, Musaad
骨髓脂肪组织（BMAT）是来源于骨髓基质干细胞（BMSCs）的独特脂肪库，调节骨稳态和能量代谢。在几种情况下观察到BMAT体积增加，例如肥胖症、2型糖尿病、骨质疏松症，并且已知其与骨脆性和骨折风险增加相关。减少BMAT蓄积的治疗方法具有临床意义。在天然化合物的筛选实验中，我们确定了白藜芦醇（RSV），一种植物来源的抗氧化剂介导的生物效应通过sirtuin相关的机制，发挥显着的影响BMAT的形成。因此，我们详细研究了RSV对耐受化的人BMSCs（hBMSC-TERT）脂肪细胞和成骨细胞分化的影响。与对照组和Sirtinol（Sirtuin抑制剂）相比，RSV（1.0 μ M）增强hBMSC-TERT的成骨细胞分化并抑制脂肪细胞分化。全局基因表达谱和蛋白质印迹分析揭示了包括粘着斑激酶（FAK）在内的许多信号通路的激活。使用（PF-573228）和AKT抑制剂（LY-294002）（5 μ M）对FAK进行药理学抑制，减少了RSV诱导的成骨细胞分化。此外，RSV降低了衰老相关分泌表型（SASP）、与衰老相关的基因标志物（P53、P16和P21）、细胞内ROS水平，并增加了保护细胞免受氧化损伤的酶（HMOX 1和SOD 3）的基因表达。与年轻供体的hBMSCs相比，RSV体外处理来自老年患者的原代hBMSCs具有高脂肪细胞和低成骨细胞分化能力，显着增强成骨细胞和减少脂肪细胞形成。RSV靶向hBMSC并抑制脂肪形成分化和衰老相关表型，因此是用于治疗BMAT形成增加的病症的潜在药剂。
Bone marrow adipose tissue (BMAT) is a unique adipose depot originating from bone marrow stromal stem cells (BMSCs) and regulates bone homeostasis and energy metabolism. An increased BMAT volume is observed in several conditions e.g. obesity, type 2 diabetes, osteoporosis and is known to be associated with bone fragility and increased risk for fracture. Therapeutic approaches to decrease the accumulation of BMAT are clinically relevant. In a screening experiment of natural compounds, we identified Resveratrol (RSV), a plant-derived antioxidant mediating biological effects via sirtuin-related mechanisms, to exert significant effects of BMAT formation. Thus, we examined in details the effects RSV on adipocytic and osteoblastic differentiation of tolermerized human BMSCs (hBMSC-TERT). RSV (1.0 mu M) enhanced osteoblastic differentiation and inhibited adipocytic differentiation of hBMSC-TERT when compared with control and Sirtinol (Sirtuin inhibitor). Global gene expression profiling and western blot analysis revealed activation of a number of signaling pathways including focal adhesion kinase (FAK). Pharmacological inhibition of FAK using (PF-573228) and AKT inhibitor (LY-294002) (5 mu M), diminished RSV-induced osteoblast differentiation. In addition, RSV reduced the levels of senescence-associated secretory phenotype (SASP), gene markers associated with senescence (P53, P16, and P21), intracellular ROS levels and increased gene expression of enzymes protecting cells from oxidative damage (HMOX1 and SOD3). In vitro treatment of primary hBMSCs from aged patients characterized with high adipocytic and low osteoblastic differentiation ability with RSV, significantly enhanced osteoblast and decreased adipocyte formation when compared to hBMSCs from young donors. RSV targets hBMSCs and inhibits adipogenic differentiation and senescence-associated phenotype and thus a potential agent for treating conditions of increased BMAT formation.