Multipotent adult progenitor cell therapy: Effect of timing and frequency on lung health in preterm lambs during inflammation

Background: Perinatal inflammation and preterm birth contribute to the development of paediatric lung diseases and their progression into adult lung diseases. Stem cells show great promise, but personalized treatment strategies are necessary to address patient variability. We hypothesize that optimal stem cell therapy should be tailored to the specific pathophysiological events contributing to prematurity-related lung diseases. Methods: Instrumented Texel ovine foetuses were exposed to intra-amniotic lipopolysaccharide (LPS 5 mg) at 125 days gestation. Multipotent adult progenitor cells (MAPC) (10 × 10⁶ cells) or saline were administered intravenously two days later. After preterm birth at 132 days gestation, foetuses were immediately mechanically ventilated and treated with MAPC or saline intravenously 4 h after birth. After 72 h of mechanical ventilation, lung morphology was analysed, and mRNA and protein levels of cell junctions, inflammatory- and developmental mediators were assessed. Results: All three MAPC regimens improved pulmonary oxygenation, increased mRAGE levels and prevented LPS-induced pulmonary oedema. Single MAPC administrations, either prenatally or postnatally, prevented the attenuated anti-inflammatory pulmonary immune response. Repeated treatment primarily exerted its effects by enhancing developmental pathways, evidenced by a more pronounced increase in alveolar epithelial cells and elevated expression of the canonical WNT ligand WNT3A. Conclusion: All three MAPC regimens improve preterm lung outcomes under inflammatory conditions. However, mechanisms underlying stem cell therapy are modulated in a time- and insult-dependent manner, highlighting the potential of stem cell therapy as personalized approach.