Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury

PLoS One. 2013;8(1):e52419. doi: 10.1371/journal.pone.0052419. Epub 2013 Jan 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Body Weight
  • Cell Membrane / metabolism
  • Collagen / metabolism
  • Cytokines / metabolism
  • Cytosol / metabolism
  • Female
  • Fetal Blood / cytology*
  • Gene Expression Regulation
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Hyperoxia / complications*
  • Lung Injury / complications*
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Lung Injury / surgery*
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / cytology*
  • NADPH Oxidases / metabolism
  • Peroxidase / metabolism
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Survival Rate
  • Time Factors
  • Vascular Endothelial Growth Factor A / metabolism


  • Cytokines
  • Vascular Endothelial Growth Factor A
  • Hepatocyte Growth Factor
  • Collagen
  • Peroxidase
  • NADPH Oxidases
  • neutrophil cytosolic factor 1

Grants and funding

This work was supported by a grant from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A102136), by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (S-2011-0317-000), and by a Samsung Biomedical Research Institute Grant (#SBRI CB11271). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.