Multipotent adult progenitor cells protect the preterm lung against perinatal inflammatory stress

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants associated with high mortality and long-term disability in survivors. The pathogenesis is multifactorial, consisting of prenatal and postnatal insults, complicating the development of new therapies. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising therapy for adverse lung outcomes. Therefore, we aimed to investigate the underlying pathophysiology of adverse lung outcomes following perinatal inflammation and the benefits of MAPC treatment for the premature lung. Instrumented ovine fetuses were intra-amniotically exposed to LPS (5mg) at 125d gestation and two days later received MAPC intravenously. At 132d gestation, comparable to 33 weeks human gestation, fetuses were delivered preterm and mechanically ventilated (MV) for 72h. LPS exposure prior to preterm birth and MV resulted in higher oxygen demands. Mechanistically, this was associated with decreased alveolar maturation and pulmonary edema accompanied by cell junction loss. MAPC therapy improved functional impairment following perinatal inflammation. This improvement was attributed to reduced pulmonary edema and enhanced distal pulmonary development. In conclusion, we demonstrated that perinatal inflamamtion, induced by antenatal LPS exposure and postnatal MV, in preterm lambs, resulted in impaired lung function and compromised lung development, which predisposes them to life long lung sequelae. MAPC therpay effectively improved pulmonary function and enhanced lung maturation and therefore is a promising approach for preterm infants to prevent inflammation driven adverse pulmonary outcomes.