title: Lineage specification of Flk-1+ progenitors is associated with divergent Sox7 expression in cardiopoiesis.
abstract: Embryonic stem cell differentiation recapitulates the diverse phenotypes of a developing embryo, traceable according to markers of lineage specification. At gastrulation, the vascular endothelial growth factor (VEGF) receptor, Flk-1 (KDR), identifies a mesoderm-restricted potential of embryonic stem cells. The multi-lineage propensity of Flk-1(+) progenitors mandates the mapping of fate-modifying co-factors in order to stratify differentiating cytotypes and predict lineage competency. Here, Flk-1-based selection of early embryonic stem cell progeny separated a population depleted of pluripotent (Oct4, Sox2) and endoderm (Sox17) markers. The gene expression profile of the Flk-1(+) population was notable for a significant upregulation in the vasculogenic Sox7 transcription factor, which overlapped with the emergence of primordial cardiac transcription factors GATA-4, Myocardin and Nkx2.5. Sorting the parental Flk-1(+) pool with the chemokine receptor CXCR4 to enrich the cardiopoietic subpopulation uncovered divergent Sox7 expression, with a 7-fold induction in non-cardiac compared to cardiac progenitors. Bioinformatic resolution sequestered a framework of gene expression relationship between Sox transcription factor family members and the Flk-1/CXCR4 axes with significant integration of beta-catenin signaling. Thus, differential Sox7 gene expression presents a novel biomarker profile, and possible regulatory switch, to distinguish cardiovascular pedigrees within Flk-1(+) multi-lineage progenitors.
authors.affiliation: Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Nelson
authors.forename: Anca
authors.initials: A
authors.lastname: Chiriac
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Faustino
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Crespo-Diaz
authors.forename: Atta
authors.initials: A
authors.lastname: Behfar
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology*; D055760:SOXF Transcription Factors / Q000145:classification / Q000378:metabolism*; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D055760:SOXF Transcription Factors; D040301:Vascular Endothelial Growth Factor Receptor-2