Phenotype disruption of umbilical cord derived MSC by cyclic mechanical stretch and hyperoxia mediated by p21

Preclinical studies provided convincing evidence that umbilical cord derived mesenchymal stem cells (UC-MSC) prevent lung injury and promote lung regeneration. We hypothesized that cyclic mechanical stretch (CMS) and hyperoxia (HOX) during mechanical ventilation account for their limited therapeutic efficacy within the clinics. UC-MSC cultures were subjected to CMS and HOX and evaluated for proliferation, cell viability and further functional properties. Reversibility of the phenotype changes was evaluated after recovery in room air following these exposures. CMS and HOX compromised cell viability and proliferation, altered phenotypic characteristics, particularly PDGFRα expression, and induced cellular senescence in UC-MSC. Effects were most pronounced for CMS plus HOX. The alterations of UC-MSC were mediated by p21 accumulation. As inhibition of p21 aggravated cell death of UC-MSC, the results indicated a cell defense mechanism to ensure survival. This assumption was underpinned by the principal reversibility of the phenotype alterations and regrowth after removal of CMS and HOX. But prolonged strongest exposures resulted in definite phenotype changes. CMS and HOX have comparable effects on UC-MSC as described for lung resident MSC. Our results explain their timely limited presence in the diseased lung after therapeutic application. Future research should therefore focus on their repetitive application.