Low-Oxygen Tension and IGF-I Promote Proliferation and Multipotency of Placental Mesenchymal Stem Cells (PMSCs) from Different Gestations via Distinct Signaling Pathways

Abstract

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.

Insulin‐like growth factor 1 can promote proliferation and osteogenic differentiation of human dental pulp stem cells via mTOR pathway

“…A value of P < 0.05 was considered to be statistically significant. Supeno et al (2013) had testified that IGF-1 acts as controlling switch for long-term proliferation of neural stem cells, and IGF-1 can promote proliferation of placental mesenchymal stem cells (PMSCs) via distinct signaling pathways (Youssef et al 2014). So we used CCK-8 assay to investigate whether IGF-1 would affect proliferation of DPSCs in vitro.…”

Insulin‐like growth factors and their potential role in cardiac epigenetics

“…In addition, for hybrid receptors which bind both insulin and IGF-I, the transmembrane subunits play a decisive role in recruiting intracellular mediators through their Tyr residues. This is common in muscle progenitors but also in fully differentiated cells [53][54][55][56][57] (Fig. 1B).…”

The Roles of Insulin-Like Growth Factors in Mesenchymal Stem Cell Niche

“…In this study, autocrine IGF-1 levels maintain an elevated baseline activity of ERK1/2 signaling required for enhanced self-renewal (higher OCT4), endodermal (higher CYP51) and mesodermal (higher SM22 α ) potential, but weakened neuronal potential (lower Nestin) [84]. Another growth factor which is basic fibroblast growth factor (bFGF) was shown to be required in maintaining stemness and proliferation in hESCs [31, 85] and in MSCs [80, 86, 87]. Further investigation showed that this bFGF effect was mediated via the IGF system that is upregulated by an autonomous expression of IGF-1R, IGF-1, and IGF-2, as shown in umbilical cord MSCs [86].…”

“…A study, in human dental pulp MSCs (hDSCs), confirmed that IGF-1R is required for MSC multipotency and can be regarded as a selection marker for stemness, just similar to OCT4 and SOX2 [89]. In placental MSCs (PMSCs), IGF-2 is upregulated by low oxygen tension and is required to maintain MSC multipotency [80, 87]. Also, in neural stem cells (NSCs), IGF-2 was shown to play an important role in maintaining self-renewal [90].…”