Low-oxygen tension and IGF-I promote proliferation and multipotency of placental mesenchymal stem cells (PMSCs) from different gestations via distinct signaling pathways.

The microenvironment of placental mesenchymal stem cells (PMSCs) is dynamic throughout gestation and determines changes in cell fate. In vivo, PMSCs initially develop in low-oxygen tension and low IGF-I concentrations, and both increase gradually with gestation. The impact of varying concentrations of IGF-I and changing oxygen tension on PMSC signaling and multipotency was investigated in PMSCs from early (preterm) and late (term) gestation human placentae. Preterm PMSCs had greater proliferative response to IGF-I, which was further enhanced by low-oxygen tension. Low-oxygen tension alone was sufficient to induce ERK1/2 phosphorylation, whereas IGF-I was required for AKT (protein kinase B) phosphorylation. Low-oxygen tension prolonged ERK1/2 and AKT phosphorylation with a slowed phosphorylation decay even in presence of IGF-I. Low-oxygen tension maintained higher levels of IGF-I receptor and insulin receptor substrate 1 that were otherwise decreased by exposure to IGF-I and induced a differential phosphorylation pattern on IGF-I receptorβ and insulin receptor substrate 1. Phosphorylation of ERK1/2 and AKT was different between the preterm and term PMSCs, and phospho-AKT, and not phospho-ERK1/2, was the major determinant of PMSC proliferation and octamer-4 levels. These studies demonstrate that low-oxygen tension regulates the fate of PMSCs from early and late gestations in response to IGF-I, both independently and dependently, via specific signal transduction mechanisms.