Abstract
Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this study was to optimize the timing of MSCs transplantation. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (90% for 2 weeks and 60% for 1 week) or normoxia after birth for 21 days. Human UCB-derived MSCs (5×105 cells) were delivered intratracheally early at postnatal day (P) 3 (HT3), late at P10 (HT10) or combined early+late at P3+10 (HT3+10). Hyperoxia-induced increase in mortality, TUNEL positive cells, ED1 positive alveolar macrophages, myeloperoxidase activity and collagen levels, retarded growth and reduced alveolarization as evidenced by increased mean linear intercept and mean alveolar volume were significantly better attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced up-regulation of both cytosolic and membrane p47phox indicative of oxidative stress, and increased inflammatory markers such as tumor necrosis factor-α, interleukin (IL) -1α, IL-1β, IL-6, and transforming growth factor-β measured by ELISA, and tissue inhibitor of metalloproteinase-1, CXCL7, RANTES, L-selectin and soluble intercellular adhesion molecule-1 measured by protein array were consistently more attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced decrease in hepatocyte growth factor and vascular endothelial growth factor was significantly up-regulated in both HT3 and HT3+10, but not in HT10. In summary, intratracheal transplantation of human UCB derived MSCs time-dependently attenuated hyperoxia-induced lung injury in neonatal rats, showing significant protection only in the early but not in the late phase of inflammation. There were no synergies with combined early+late MSCs transplantation.
Highlights
Recent improvements in neonatal intensive care medicine have resulted in marked improvements in the survival of the premature infants [1]
In the present study, prolonged exposure of newborn rat pups to hyperoxia for 3 weeks increased mortality, retarded growth, and developed lung injuries similar to those seen in the premature human infants with bronchopulmonary dysplasia (BPD) [23,24], exhibiting decreased alveolarization as evidenced by increased MLI and alveolar volume [25], and significantly increased TUNEL positive cells [26]
Hyperoxic exposure was extended to 3 weeks to guarantee the comparable time span after mesenchymal stem cells (MSCs) transplantation at P10, and the oxygen concentration during the third week was reduced from 90% to 60% because of the concern about increased mortality due to prolonged high oxygen exposure
Summary
Recent improvements in neonatal intensive care medicine have resulted in marked improvements in the survival of the premature infants [1]. We have shown that local intratracheal but not systemic intraperitoneal xenotransplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates hyperoxia induced lung injuries such as impaired alveolarization, increased apoptosis and fibrosis in the immunocompetent neonatal rats [7]. These protective effects of stem cell transplantation were dose dependent [8]. Overall, these findings suggest that human UCB derived MSCs transplantation could be a novel therapeutic modality for BPD. While the administration of human UCB-derived MSCs at postnatal day (P) 5 was effective in our previous studies [7,8], the optimal timing for their administration has not been determined yet
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