Abstract
BackgroundMesenchymal stem cells (MSCs) attenuate lung injury in experimental models of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1), a chemokine secreted by MSCs, modulates angiogenesis and stem cell recruitment. Here we tested the hypothesis that SDF-1 mediates MSC protective effects in experimental BPD by modulating angiogenesis.MethodsSDF-1 was knocked down in MSCs using lentiviral vectors carrying anti-SDF-1 short hairpin RNA (MSC-SDF KD). Non-silencing short hairpin RNA was used as control (MSC-NS control). Newborn rats exposed to normoxia or hyperoxia (FiO2 = 0.85) for 3 weeks, were randomly assigned to receive a single intra-tracheal injection (IT) of MSC-NS control or MSC-SDF KD (1 × 106 cells/50 μl) or placebo on postnatal day 7. The degree of alveolarization, lung angiogenesis, inflammation, and pulmonary hypertension (PH) were assessed at postnatal day 21.ResultsAdministration of IT MSC-NS control improved lung alveolarization, angiogenesis and inflammation, and attenuated PH in newborn rats with hyperoxia-induced lung injury (HILI). In contrast, knockdown of SDF-1 in MSCs significantly reduced their beneficial effects on alveolarization, angiogenesis, inflammation and PH.ConclusionsThe therapeutic benefits of MSCs in neonatal HILI are in part mediated by SDF-1, through anti-inflammatory and angiogenesis promoting mechanisms. Therapies directly targeting this chemokine may provide a novel strategy for the treatment of BPD.
Highlights
Mesenchymal stem cells (MSCs) attenuate lung injury in experimental models of bronchopulmonary dysplasia (BPD)
Our results indicate that the therapeutic benefits of MSC administration in experimental BPD are in part mediated by Stromal derived factor-1 (SDF-1), through pro-angiogenic and antiinflammatory mechanisms
In order to investigate the role of SDF-1 in MSC regenerative potential in neonatal hyperoxiainduced lung injury (HILI), rat MSCs were transduced with lentiviral vectors expressing short hairpin RNA against SDF-1 or non-silencing short hairpin RNA as control
Summary
Animals Pregnant Sprague Dawley rats were purchased from Charles River Laboratories (Wilmington, MA). Neonatal hyperoxia model Sprague Dawley pups assigned to normoxia (RA: 21% O2) or hyperoxia (85% O2) from postnatal day 1 to postnatal day 21 were randomly assigned to receive IT injections of MSC expressing anti-SDF-1 (MSC-SDF KD), non-silencing control short hairpin RNA (MSC-NS control), or phosphate buffered saline as placebo (PL) on postnatal day 7. This route was chosen as prior studies have demonstrated that IT MSCs are more effective than systemically administered cells [23]. P values less than 0.05 were considered statistically significant
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