Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats.
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.
van Haaften
Timothy
T
Department of Pediatrics, Women and Children Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
Byrne
Roisin
R
Bonnet
Sebastien
S
Rochefort
Gael Y
GY
Akabutu
John
J
Bouchentouf
Manaf
M
Rey-Parra
Gloria J
GJ
Galipeau
Jacques
J
Haromy
Alois
A
Eaton
Farah
F
Chen
Ming
M
Hashimoto
Kyoko
K
Abley
Doris
D
Korbutt
Greg
G
Archer
Stephen L
SL
Thébaud
Bernard
B
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