title: 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.
authors.affiliation: Systems Biology Ireland, National University of Ireland Galway, Galway, Ireland; Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Fábián
authors.affiliation: Systems Biology Ireland, National University of Ireland Galway, Galway, Ireland; School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Sivaramakrishnan
authors.initials: S
authors.lastname: Ramadurai
authors.affiliation: Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland.
authors.forename: Georgina
authors.initials: G
authors.lastname: Shaw
authors.affiliation: Systems Biology Ireland, National University of Ireland Galway, Galway, Ireland; School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Nasheuer
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Cormac
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Systems Biology Ireland, National University of Ireland Galway, Galway, Ireland; Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland. Electronic address: frank.barry@nuigalway.ie.
authors.forename: Frank
authors.initials: F
authors.lastname: Barry
mesh_terms: D015687:Cell Hypoxia; D049109:Cell Proliferation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015854:Up-Regulation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016222:Fibroblast Growth Factor 2; D010100:Oxygen