期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 180, 期 11, 页码 1131-1142出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.200902-0179OC
关键词
stem cells; aging; lung; oxygen
资金
- Canada Foundation for Innovation
- Alberta Heritage Foundation for Medical Research (AHFMR)
- Canadian Institutes for Health Research (CIHR)
- Canadian Stem Cell Network
- Stollery Children's Hospital Foundation
- Canada Research Chair
- Tomorrow's Research Cardiovascular Health Professionals (TORCH)
- Maternal Fetal Neonatal Health Training Program sponsored by CIHR-IHDCYH
- NIH-RO1-HL071115
- [NlH-RO1-HL071115]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL071115] Funding Source: NIH RePORTER
Rationale: Bronchopulmonary dysplasia (BIRD) 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. Objectives: 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. Measurements and Main Results: In vitro, BMSCs developed immuno-phenotypic 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.
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