Basic fibroblast growth factor modifies the hypoxic response of human bone marrow stromal cells by ERK-mediated enhancement of HIF-1α activity

Abstract

Human bone marrow stromal cells (hBMSCs, also known as bone marrow-derived mesenchymal stem cells) are promising tools for the cellular therapy of human pathologies related to various forms of hypoxia. Although the current concepts of their clinical use include the expansion of hBMSC in standard cell culture conditions, the effect of the mitogen-driven ex vivo expansion on the adaptation to the hypoxic environment is unknown. Here, we provide data that the basic fibroblast growth factor (FGF2) enhances the induction of a wide range of hypoxia-related adaptive genes in hypoxic hBMSCs. We identified that the FGF2 signal is transmitted by the ERK pathway similar to that of hypoxia that also utilises the distal elements of the same signalling machinery including the extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase kinases (MEK1/2) in hBMSCs. We found that the simultaneous activation of ERK1/2 by FGF2 and hypoxia transforms the activation dynamics from oscillatory into sustained one. Activated ERKs co-localise with stabilised hypoxia inducible factor-1α (HIF-1α) followed by the reduction of its nuclear mobility as well as increased DNA binding capacity leading to the up-regulation of hypoxia-adaptive genes. Our findings indicate that the status of the ERK pathway has significant impacts on the molecular adaptation of hBMSCs to the hypoxic milieu.