Long-term reparative effects of mesenchymal stem cell therapy following neonatal hyperoxia-induced lung injury.

BACKGROUND: Mesenchymal stem cell (MSC) therapy may prevent neonatal hyperoxia-induced lung injury (HILI). There are, however, no clear data on the therapeutic efficacy of MSC therapy in established HILI, the duration of the reparative effects, and the exact mechanisms of repair. The main objective of this study was to evaluate whether the long-term reparative effects of a single intratracheal (IT) dose of MSCs or MSC-conditioned medium (CM) are comparable in established HILI. METHODS: Newborn rats exposed to normoxia or hyperoxia from postnatal day (P)2)-P16 were randomized to receive IT MSCs, IT CM, or IT placebo (PL) on P9. Alveolarization and angiogenesis were evaluated at P16, P30, and P100. RESULTS: At all time periods, there were marked improvements in alveolar and vascular development in hyperoxic pups treated with MSCs or CM as compared with PL. This was associated with decreased expression of inflammatory mediators and an upregulation of angiogenic factors. Of note, at P100, the improvements were more substantial with MSCs as compared with CM. CONCLUSION: These data suggest that acute effects of MSC therapy in HILI are mainly paracrine mediated; however, optimum long-term improvement following HILI requires treatment with the MSCs themselves or potentially repetitive administration of CM.

Antagonism of CXCR7 attenuates chronic hypoxia-induced pulmonary hypertension.

INTRODUCTION: Chemokines may directly participate in the pathogenesis of neonatal chronic hypoxia-induced pulmonary hypertension (PH). Although stromal-derived factor-1 (SDF-1) has been shown to be involved in PH, the role of its most recently discovered receptor, chemokine receptor type 7 (CXCR7), remains unclear. We sought to determine whether antagonism of the CXCR7 receptor would decrease pulmonary vascular remodeling in newborn mice exposed to chronic hypoxia by decreasing pulmonary vascular cell proliferation. METHODS: Neonatal mice were exposed to hypoxia (fractional inspired oxygen concentration = 0.12) or room air (RA) for 2 wk. After 1 wk of exposure, mice received daily injections of placebo or a CXCR7 antagonist (CCX771) from postnatal day 7 (P7) to P14. Right ventricular systolic pressure (RVSP), the ratio of the weight of the right ventricle to left ventricle + septum (RV/LV + S), and pulmonary vascular cell proliferation and remodeling were determined at P14. RESULTS: As compared with mice exposed to RA, hypoxia placebo mice had a significant increase in the lung protein expression of CXCR7. Although hypoxic placebo-treated mice had a significant increase in RVSP, RV/LV+S, and pulmonary vascular cell proliferation and remodeling, the administration of CCX771 markedly decreased these changes. DISCUSSION: These results indicate that antagonism of CXCR7 may be a potent strategy to decrease PH and vascular remodeling.