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 (5×10(5) 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 p47(
phox) 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.