Dose-dependent effects of human umbilical cord-derived mesenchymal stem cell treatment in hyperoxia-induced lung injury of neonatal rats

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent stromal cells that have been reported to possess great potential for the treatment of bronchopulmonary dysplasia (BPD). OBJECTIVE: Our study aims to assess the effects of three different doses of intraperitoneal administration of human umbilical cord-derived MSCs (hUC-MSCs) on a hyperoxia-induced BPD model of newborn rat. METHODS: Neonatal Sprague Dawley (SD) rats were reared in either hyperoxia (75% O2) or room air (RA) from postnatal days (PN) 1-14. At PN5, hUC-MSCs (1 × 106, 5× 106,or 1× 107 cells per pup) were given intraperitoneally to newborn rats exposed to 75% O2 from birth; the controls received an equal volume of normal saline (NS). At PN14, the lung tissues, serum, and bronchoalveolar fluid (BALF) were collected for histologic examination, wet/dry (W/D) weight ratio analysis, engraftment, myeoloperoxidase (MPO) activity analysis, cytokine analysis, and western blot analysis of protein expression. RESULTS: Compared to rat pups reared in RA, rat pups reared in hyperoxia had a significant lower survival rate (53.3%) (P < 0.01). Hyperoxia-exposed rats exhibited pulmonary inflammation accompanied by alveolar-capillary leakage, neutrophile infiltration, augmented myeloperoxidase (MPO) activity, prominent alveolar simplification, and increased mean linear intercept (MLI), which was ameliorated by hUC-MSCs treatment. Increased oxidative stress and inflammatory cytokine production were also reduced. Importantly, the expression of Fas, an apoptosis-associated protein that was increasingly expressed in hyperoxia-exposed rats (P < 0.05), was downregulated after administration of hUC-MSCs (P < 0.05). CONCLUSIONS: Our results suggest that intraperitoneal administration of high number hUC-MSCs (1 × 107 cells) may represent an effective modality for the treatment of hyperoxia-induced BPD in neonatal rats.