title: Fibrinogen Induces RUNX2 Activity and Osteogenic Development from Human Pluripotent Stem Cells.
abstract: Pluripotent stem cells, both human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC), provide an important resource to produce specialized cells such as osteogenic cells for therapeutic applications such as repair or replacement of injured, diseased or damaged bone. hESCs and iPSCs can also be used to better define basic cellular and genetic mechanisms that regulate the earliest stages of human bone development. However, current strategies to mediate osteogenic differentiation of hESC and iPSC are typically limited by the use of xenogeneic components such as fetal bovine serum (FBS) that make defining specific agents that mediate human osteogenesis difficult. Runt-related transcription factor 2 (RUNX2) is a key regulator required for osteogenic differentiation. Here, we used a RUNX2-YFP reporter system to characterize the novel ability of fibrinogen to mediate human osteogenic development from hESC and iPSC in defined (serum-free) conditions. These studies demonstrate that fibrinogen mediates significant osteo-induction potential. Specifically, fibrinogen binds to the surface integrin (α9β1) to mediate RUNX2 gene expression through the SMAD1/5/8 signaling pathway. Additional studies characterize the fibrinogen-induced hESC/iPSC-derived osteogenic cells to demonstrate these osteogenic cells retain the capacity to express typical mature osteoblastic markers. Together, these studies define a novel fibrinogen-α9β1-SMAD1/5/8-RUNX2 signaling axis can efficiently induce osteogenic differentiation from hESCs and iPSCs. Stem Cells 2016;34:2079-2089.
authors.affiliation: Department of Restorative Sciences, School of Dentistry, University of Minnesota, Minnesota Dental Research Center for Biomaterials and Biomechanics, Minneapolis, Minnesota, 55455, USA.|Division of Basic Sciences, Department of Diagnostic and Biological Sciences, School of Dentistry.
authors.forename: Fahad
authors.initials: F
authors.lastname: Kidwai
authors.affiliation: Division of Basic Sciences, Department of Diagnostic and Biological Sciences, School of Dentistry.
authors.forename: Jessica
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota, 55455, USA.|Department of Medicine, University of California - San Diego, La Jolla, California, 92093, USA.
authors.forename: Dan S
authors.initials: DS
authors.lastname: Kaufman
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D005340:Fibrinogen / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors
chemical_list: D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D016023:Integrins; D051785:Smad Proteins; C113256:integrin alpha 9 beta 1; D005340:Fibrinogen
keywords: Fibrinogen; Human embryonic stem cells; Human induced pluripotent stem cells; Osteoblast; RUNX2; SMAD pathway; Yellow fluorescent protein; α9β1