Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Rejuvenation Res. 2020 Dec;23(6):453-464. doi: 10.1089/rej.2019.2260. Epub 2020 Apr 28.
Sirtuin 3 (SIRT3) is a deacetylase important for antioxidant protection, cell longevity, and aging. We hypothesized that SIRT3 improve oxidative resistance of aged cells and improve cell therapy in aged patients. , the proliferation and oxidative resistance of human mesenchymal stem cells (hMSCs) significantly declined with age. The expression and activity of antioxidant enzymes, including catalase (CAT) and manganese superoxide dismutase (MnSOD), increased after transfection of in hMSCs from older donors (O-hMSCs). The protein level of Forkhead box O3a (FOXO3a) in nucleus increased after SIRT3 overexpression. The antioxidant capacity of O-hMSCs increased after SIRT3 overexpression. 3-Amino-1,2,4-triazole (3-AT, CAT inhibitor) or diethyldithiocarbamate (DETC, SOD inhibitor) that was used to inhibit CAT or SOD activity significantly blocked the antioxidant function of SIRT3. When two inhibitors were used together, the antioxidant function of SIRT3 almost disappeared. Following myocardial infarction and intramyocardial injections of O-hMSCs in rats , the survival rate of O-hMSCs increased by transfection. The cardiac function of rats was improved after SIRT3-overexpressed O-hMSC transplantation. The infarct size, collagen content, and expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 decreased. Besides, the protein level of vascular endothelial growth factor A and vascular density increased after cell transplantation with SIRT3-modified O-hMSCs. These results indicate that damage resistance of hMSCs decline with age and SIRT3 might protect O-hMSCs against oxidative damage by activating CAT and MnSOD through transferring FOXO3a into nucleus. Meanwhile, the therapeutic effect of aged hMSC transplantation can be improved by SIRT3 overexpression.
Sirtuin 3（SIRT3）是一种重要的去乙酰化酶，对于抗氧化保护、细胞长寿和衰老具有重要作用。我们假设 SIRT3 可以提高衰老细胞的抗氧化能力，并改善老年患者的细胞治疗效果。研究发现，随着年龄的增长，人骨髓间充质干细胞（hMSCs）的增殖和抗氧化能力显著下降。在来自老年供体（O-hMSCs）的 hMSCs 中转染 后，抗氧化酶（包括过氧化氢酶（CAT）和锰超氧化物歧化酶（MnSOD））的表达和活性增加。SIRT3 过表达后，核内 Forkhead box O3a（FOXO3a）的蛋白水平增加。O-hMSCs 的抗氧化能力在 SIRT3 过表达后增加。使用 3-氨基-1,2,4-三唑（3-AT，CAT 抑制剂）或二乙基二硫代氨基甲酸盐（DETC，SOD 抑制剂）抑制 CAT 或 SOD 活性可显著阻断 SIRT3 的抗氧化功能。当两种抑制剂一起使用时，SIRT3 的抗氧化功能几乎消失。在大鼠心肌梗死和心肌内注射 O-hMSCs 后， 通过 转染，O-hMSCs 的存活率增加。SIRT3 过表达 O-hMSC 移植后改善了大鼠的心脏功能。梗死面积、胶原含量以及基质金属蛋白酶 2（MMP2）和 MMP9 的表达水平降低。此外，SIRT3 修饰的 O-hMSCs 移植后，血管内皮生长因子 A 和血管密度的蛋白水平增加。这些结果表明，hMSCs 的损伤抵抗能力随年龄增长而下降，SIRT3 可能通过将 FOXO3a 转位到核内来激活 CAT 和 MnSOD，从而保护 O-hMSCs 免受氧化损伤。同时，通过 SIRT3 过表达可以提高老年 hMSC 移植的治疗效果。
