Influence of Donor and Recipient Gender on Telomere Maintenanceafter Umbilical Cord Blood Cell Transplantation: A Study by the GruppoItaliano Trapianto Di Midollo Osseo

Physiological loss of telomerase activity in adult life determines progressive telomere length (TL) shortening. Inflammation and oxidative damage are established causes of TL loss; moreover, males have shorter telomeres compared to females. Despite these notions, mechanisms regulating TL maintenance are poorly defined. As umbilical cord blood (UCB) cells harbor very long telomeres, not yet exposed to environmental damages, UCB transplantation (UCB-T) provides a unique experimental setting to study determinants of TL in humans. TL dynamics was analyzed on peripheral blood mononucleated cells (MNCs) from 36 patients (median age: 42 yrs.) undergoing UCB-T. TL was studied at a median of 20 months since UCB-T. A significantly longer TL (mean 8,698 bp, range 6521-11960) was documented in UCB-T recipients compared to age-matched healthy controls (mean 7,396 bp, range 4,375-11,108) (p<0.01). Among variables potentially influencing TL maintenance, including recipient features, graft type, transplant procedure, and engraftment kinetics, only donor/recipient gender combination was associated to TL, with longest TL in females receiving a male UCB (mean 10,063 bp, range 8,381-11,960). To further investigate this trend, telomerase activation was assessed in vitro. Experiments showed that telomerase subunits were preferentially up-regulated in male-derived bone marrow MNCs exposed ex-vivo to estradiol as compared to female MNCs. This implies an increased sensitivity of male-derived MNCs to telomerase activation induced by estradiol. The results suggest that extrinsic and modifiable factors such as hormonal status and female milieu could be major determinants of TL in humans providing the rationale for investigating hormonal-based approaches to counteract telomere erosion and aging-related diseases.