Low Oxygen Tension Modulates the Insulin-Like Growth Factor-1 or -2 Signaling via Both Insulin-Like Growth Factor-1 Receptor and Insulin Receptor to Maintain Stem Cell Identity in Placental Mesenchymal Stem Cells

Abstract

Placental mesenchymal stem cells (PMSCs) are readily available multipotent stem cells for potential use in regenerative therapies. For this purpose, PMSCs must be maintained in culture conditions that mimic the in vivo microenvironment. IGFs (IGF-1 and IGF-2) and oxygen tension are low in the placenta in early gestation and increase as pregnancy progresses. IGFs bind to two receptor tyrosine kinases, the IGF-1 receptor (IGF-1R) and the insulin receptor (IR), and their hybrid receptors. We hypothesized that IGF-1 and IGF-2 signal via distinct signaling pathways under low-oxygen tension to maintain PMSC multipotency. In preterm PMSCs, low-oxygen tension increased the expression of IGF-2 and reduced IGF-1. IGF-1 stimulated higher phosphorylation of IGF-1Rβ, ERK1/2, and AKT, which was maintained at steady lower levels by low oxygen tension. PMSC proliferation was increased by IGF-1 more than IGF-2,and was potentiated by low-oxygen tension. This IGF/low oxygen tension-mediated proliferation was receptor dependent because neutralization of the IGF-1R inhibited PMSC proliferation in the presence of IGF-1 and the IR in presence of IGF-2. These findings suggest that both IGF-1R and the IR can participate in mediating IGF signaling in maintaining PMSCs multipotency. We conclude that low-oxygen tension can modify the IGF-1 or IGF-2 signaling via the IGF-1R and IR in PMSCs.

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

“…For a more detailed review on insulin and IGF receptor signaling in neural stem cells, please see Ziegler et al (2015) [92]. We verified the role of IR-A in PMSC, where we showed an elevated expression level of IR-A versus IR-B; and both IGF-1 and IGF-2 promote increased proliferation and self-renewal with a requirement that both IGF-1R and IR must be present [80]. Although IGF-1R and IR can form hybrid receptors, the role of hybrid receptor in maintaining stem cell fate (ESCs or MSCs) and pluripotency is yet to be confirmed.…”

“…MSCs isolated from different tissues, such as bone marrow, adipose tissue, placental chorionic villi, and fetal membranes, express and secrete IGF-1 and/or IGF-2 in vitro [80–83]. It was shown that ectopic IGF-1 expression in MSCs enhances their proliferation with lower apoptosis [84].…”

“…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].…”

Effect of stromal cell-derived factor-1 on myocardial apoptosis and cardiac function recovery in rats with acute myocardial infarction

“…Various differentiation inducing factors such as stromal cell-derived factor-1 (SDF-1), insulin like growth factor-1 and granulocyte colony-stimulating factor, play a key role in stem cell directional migration and differentiation (4,5). However, previous studies focused on the differentiation-inducing factor promoting the stem cell therapy effect (6,7).…”