Department of Cardiology, Guangzhou Red Cross Hospital, Medical College of Ji-Nan University, 396 Tongfuzhong Road, Haizhu District, 510220, Guangzhou, China.
Department of Cardiology, Dahua Hospital, 901 Laohumin Road, Xuhui District, 200237, Shanghai, China.
Lab Invest. 2019 Nov;99(11):1661-1688. doi: 10.1038/s41374-019-0290-1. Epub 2019 Jul 10.
Growth differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in rejuvenating old stem cells after acute injury in the elderly population. This study aimed to evaluate the effects of telomerase reverse transcriptase (TERT) on GDF11-mediated rejuvenation of senescent late-outgrowth endothelial progenitor cells (EPCs), defined as VEGFR2/CD133 cells, in elderly patients with acute myocardial infarction (AMI). We compared the quantity and capabilities of VEGFR2/CD133 cells from old (>60 years), middle-aged (45-60 years), and young (<45 years) AMI patients. The decline in circulating count and survival of VEGFR2/CD133 cells with age was accompanied by decrease in their TERT and GDF11 expression levels in patients with AMI. Further, upregulation of TERT could trigger GDF11-mediated rejuvenation of old VEGFR2/CD133 cells by renewing their survival and angiogenic abilities through activation of canonical (Smad2/3) and noncanonical (eNOS) signaling pathways. Depletion of GDF11 or TERT caused senescence of young VEGFR2/CD133 cells leading to impaired vascular function and angiogenesis in vitro and in vivo, whereas adTERT and rhGDF11 rescued this senescence. TERT cooperates with GDF11 to enhance regenerative capabilities of old VEGFR2/CD133 cells. When combined with TERT, GDF11 may represent a potential therapeutic target for the treatment of elderly patients with MI.
生长分化因子 11（GDF11）是转化生长因子β超家族成员，其在老年人群急性损伤后使衰老干细胞再生的作用存在争议。本研究旨在评估端粒酶逆转录酶（TERT）对 GDF11 介导的老年急性心肌梗死（AMI）患者晚期血管内皮祖细胞（EPC），即 VEGFR2/CD133 细胞衰老的影响。我们比较了老年（>60 岁）、中年（45-60 岁）和年轻（<45 岁）AMI 患者中 VEGFR2/CD133 细胞的数量和功能。随着年龄的增长，循环计数和 VEGFR2/CD133 细胞的存活率下降，同时伴有 AMI 患者 TERT 和 GDF11 表达水平降低。此外，上调 TERT 可通过激活经典（Smad2/3）和非经典（eNOS）信号通路，恢复其存活和血管生成能力，从而引发 GDF11 介导的衰老的 VEGFR2/CD133 细胞的年轻化。GDF11 或 TERT 的耗竭导致年轻的 VEGFR2/CD133 细胞衰老，导致体外和体内血管功能和血管生成受损，而 adTERT 和 rhGDF11 则可挽救这种衰老。TERT 与 GDF11 合作增强了衰老的 VEGFR2/CD133 细胞的再生能力。当与 TERT 结合时，GDF11 可能成为治疗老年 AMI 患者的潜在治疗靶点。
