title: Critical role of vascular endothelial growth factor secreted by mesenchymal stem cells in hyperoxic lung injury.
abstract: Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) protects against neonatal hyperoxic lung injury by a paracrine rather than a regenerative mechanism. However, the role of paracrine factors produced by the MSCs, such as vascular endothelial growth factor (VEGF), has not been delineated. This study examined whether VEGF secreted by MSCs plays a pivotal role in protecting against neonatal hyperoxic lung injury. VEGF was knocked down in human UCB-derived MSCs by transfection with small interfering RNA specific for human VEGF. The in vitro effects of MSCs with or without VEGF knockdown or neutralizing antibody were evaluated in a rat lung epithelial (L2) cell line challenged with H2O2. To confirm these results in vivo, newborn Sprague-Dawley rats were exposed to hyperoxia (90% O2) for 14 days. MSCs (1 × 10(5) cells) with or without VEGF knockdown were administered intratracheally at postnatal Day 5. Lungs were serially harvested for biochemical and histologic analyses. VEGF knockdown and antibody abolished the in vitro benefits of MSCs on H2O2-induced cell death and the up-regulation of inflammatory cytokines in L2 cells. VEGF knockdown also abolished the in vivo protective effects of MSCs in hyperoxic lung injury, such as the attenuation of impaired alveolarization and angiogenesis, reduction in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive and ED-1-positive cells, and down-regulation of proinflammatory cytokine levels. Our data indicate that VEGF secreted by transplanted MSCs is one of the critical paracrine factors that play seminal roles in attenuating hyperoxic lung injuries in neonatal rats.
authors.affiliation: 1 Department of Pediatrics, Samsung Medical Center, and.
authors.forename: Yun Sil
authors.initials: YS
authors.lastname: Chang
authors.forename: So Yoon
authors.initials: SY
authors.lastname: Ahn
authors.forename: Hong Bae
authors.initials: HB
authors.lastname: Jeon
authors.forename: Dong Kyung
authors.initials: DK
authors.lastname: Sung
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Kim
authors.forename: Se In
authors.initials: SI
authors.lastname: Sung
authors.forename: Hye Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Choi
authors.forename: Won Il
authors.initials: WI
authors.lastname: Oh
authors.forename: Won Soon
authors.initials: WS
authors.lastname: Park
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000737:chemistry; D002460:Cell Line; D017690:Cell Transplantation; D005312:Fetal Blood / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D018496:Hyperoxia / Q000378:metabolism*; D007249:Inflammation; D055370:Lung Injury / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010100:Oxygen / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D006861:Hydrogen Peroxide; D010100:Oxygen
keywords: cell transplantation; lung injury; newborn; stem cells; vascular endothelial growth factor