Preventive application of lung growth factors and lack of attenuation of phenotype disruption of lung resident MSC from preterm infants by hyperoxia

BACKGROUND: Phenotype disruption of lung resident mesenchymal stem cells (MSC) is a key event in the pathogenesis of bronchopulmonary dysplasia (BPD). Hyperoxia (HOX) constitutes one major harmful factor resulting in growth arrest and changes of functional properties including downregulation of PDGFRalpha. FGF-10, HGF, IGF-1 and PDGF-AA constitute promising cytokines to preserve lung growth. We studied their preventive application before HOX exposure of MSC cultures. RESULTS: As described before, HOX inhibited spontaneous proliferation of MSC and induced cell death. Growth inhibition was larger at HOX80% than at HOX40%. The one-time preventive application of FGF-10, HGF, IGF-1 or PDGF-AA in therapeutic dosage or the repetitive application during HOX (40% or 80%) did not attenuate the growth inhibition and cell death induction by HOX even during the milder HOX40% exposure. Furthermore, the phenotype disruption with downregulation of PDGFRalpha as critical hallmark event remained unchanged. CONCLUSION: Our data indicate that the deleterious effects of HOX to lung resident MSC are that pronounced that single lung growth promoting cytokines cannot attenuate their phenotype disruption, growth inhibition and cell death by HOX. The results demand focus on MSC functionality when the therapeutic potential of lung growth promoting factors and other therapeutics intended to prevent BPD is studied.

• Holzfurtner, L.
• Behnke, J.
• Korte, P.
• Goetz, M. J.
• Petzinger, J.
• Windhorst, A. C.
• Shahzad, T.
• Rivetti, S.
• Dong, Y.
• Bellusci, S.
• Ehrhardt, H.