title: Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats.
abstract: BACKGROUND
  Bronchopulmonary dysplasia (BPD) and emphysema are characterized by arrested alveolar development or loss of alveoli; both are significant global health problems and currently lack effective therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) prevent adult lung injury, but their therapeutic potential in neonatal lung disease is unknown.
  
  
  OBJECTIVE
  We hypothesized that intratracheal delivery of BMSCs would prevent alveolar destruction in experimental BPD.
  
  
  METHODS
  In vitro, BMSC differentiation and migration were assessed using co-culture assays and a modified Boyden chamber. In vivo, the therapeutic potential of BMSCs was assessed in a chronic hyperoxia-induced model of BPD in newborn rats.
  
  
  RESULTS
  In vitro, BMSCs developed immunophenotypic and ultrastructural characteristics of type II alveolar epithelial cells (AEC2) (surfactant protein C expression and lamellar bodies) when co-cultured with lung tissue, but not with culture medium alone or liver. Migration assays revealed preferential attraction of BMSCs toward oxygen-damaged lung versus normal lung. In vivo, chronic hyperoxia in newborn rats led to air space enlargement and loss of lung capillaries, and this was associated with a decrease in circulating and resident lung BMSCs. Intratracheal delivery of BMSCs on Postnatal Day 4 improved survival and exercise tolerance while attenuating alveolar and lung vascular injury and pulmonary hypertension. Engrafted BMSCs coexpressed the AEC2-specific marker surfactant protein C. However, engraftment was disproportionately low for cell replacement to account for the therapeutic benefit, suggesting a paracrine-mediated mechanism. In vitro, BMSC-derived conditioned medium prevented O(2)-induced AEC2 apoptosis, accelerated AEC2 wound healing, and enhanced endothelial cord formation.
  
  
  CONCLUSIONS
  BMSCs prevent arrested alveolar and vascular growth in part through paracrine activity. Stem cell-based therapies may offer new therapeutic avenues for lung diseases that currently lack efficient treatments.
authors.affiliation: Department of Pediatrics, Women and Children Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: van Haaften
authors.forename: Roisin
authors.initials: R
authors.lastname: Byrne
authors.forename: Sebastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Gael Y
authors.initials: GY
authors.lastname: Rochefort
authors.forename: John
authors.initials: J
authors.lastname: Akabutu
authors.forename: Manaf
authors.initials: M
authors.lastname: Bouchentouf
authors.forename: Gloria J
authors.initials: GJ
authors.lastname: Rey-Parra
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Farah
authors.initials: F
authors.lastname: Eaton
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Doris
authors.initials: D
authors.lastname: Abley
authors.forename: Greg
authors.initials: G
authors.lastname: Korbutt
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001853:Bone Marrow; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D017079:Exercise Tolerance; D018496:Hyperoxia; D006976:Hypertension, Pulmonary / Q000517:prevention & control; D055370:Lung Injury / Q000517:prevention & control*; D059630:Mesenchymal Stem Cells; D011650:Pulmonary Alveoli / Q000254:growth & development* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis