Review Article

Using Cell-Based Strategies to Break the Link between Bronchopulmonary Dysplasia and the Development of Chronic Lung Disease in Later Life

Table 1

Studies examining the therapeutic effect of stem/progenitor cells in experimental models of neonatal chronic lung disease.

Experimental modelTherapeutic cell or productOutcomesSuggested mechanismReferences

Bone marrow-derived MSCs (i.t.)Improved survival
Improved alveolar structure/prevented alveolar arrest
Prevented vascular growth arrest
Improved exercise capacity
Reduced pulmonary hypertension
Engraftment as AT2
Paracrine mechanisms
[48]
Bone marrow-derived MSCs or CdM (i.v.)Improved alveolar structure/prevented alveolar arrest
Attenuated inflammation
Prevented vascular growth arrest
Prevented pulmonary hypertension
Paracrine mechanisms
Immunomodulatory effects
[54]
Bone marrow-derived MSCs or CdM (i.v.)Increased number of BASCs
Improved alveolar structure/prevented alveolar arrest
Stimulation of BASCs
Paracrine mechanisms
[55]
Hyperoxia-induced neonatal lung injuryBone marrow-derived MSCs (i.p.)Improved survival
Improved alveolar structure/prevented alveolar arrest
Attenuated inflammation
Inhibited lung fibrosis
Engraftment as AT2
Reduction in ECM remodeling and fibrosis gene expression (TGF- 1, collagen 1 , TIMP-1)
Anti-inflammatory effects
[56]
Bone marrow-derived MSC-CdM (i.v.)Improved alveolar structure
Attenuated myofibroblast infiltration
Improved lung function
Reversed pulmonary hypertention and RV hypertrophy
Attenuated pulmonary arterial remodeling
Rescued loss of pulmonary blood vessels
Paracrine mechanisms
Cytoprotective effects
Activation of BASCs
[57]
hUCB-derived MSCs (i.t.)Improved survival and growth restriction
Improved alveolar structure
Attenuated lung fibrosis, inflammation, and ROS activity
Paracrine anti-inflammatory, antifibrotic and antioxidative effects[59, 60]
hUCB-derived MSCs and MSC-CdM (i.t.)
Umbilical cord-derived PCs and PC-CdM (i.t.)
Prevented and restored impaired alveolar growth
Improved lung function and exercise capacity
Prevented impaired lung angiogenesis
Prevented pulmonary arterial wall remodeling and RV hypertrophy
Persistent benefit on lung architecture and exercise capacity at 6 months
No adverse effects on lung structure in treated control animals at 6 months
Paracrine mechanisms[58]
BMDACs (i.v.)Improved alveolar structure
Improved vascular growth
Paracrine mechanisms[72]

LPS-induced (i.a.) neonatal lung injury hAECs (i.t.; i.v.) Improved alveolar structure
Increased surfactant protein expression
Attenuated inflammation
Immunomodulatory effects[73]

Acronyms: AT2: alveolar epithelial type 2; BASC: bronchioalveolar stem cell; BMDAC: bone marrow-derived angiogenic cell; CdM: conditioned media; ECM: extracellular matrix; hAEC: human amnion epithelial cell; hUCB: human umbilical cord blood; i.a.: intraamniotic; i.p.: intraperitoneal; i.t.: intratracheal; i.v.: intravenous; LPS: lipopolysaccharide; MSC: mesenchymal stem cell; PC: perivascular cell; ROS: reactive oxygen species; RV: right ventricle; TGF- 1: transforming growth factor- 1; TIMP1: tissue inhibitor of metalloproteinase 1.