TERT assists GDF11 to rejuvenate senescent VEGFR2/CD133 cells in elderly patients with myocardial infarction.

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.