Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury.
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.
Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Yun Sil
YS
Chang
Soo Jin
SJ
Choi
So Yoon
SY
Ahn
Dong Kyung
DK
Sung
Se In
SI
Sung
Hye Soo
HS
Yoo
Won Il
WI
Oh
Won Soon
WS
Park
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000150:complications*; D055370:Lung Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D019255:NADPH Oxidases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D003094:Collagen; D009195:Peroxidase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1