Lineage specification of Flk-1+ progenitors is associated with divergent Sox7 expression in cardiopoiesis

Abstract

SUMMARY 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 gene expression relationships between Sox transcription factor family members and the Flk-1/CXCR4 axes with significant integration of β-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.

Geometric Control of Cardiomyogenic Induction in Human Pluripotent Stem Cells

“…A direct link between SOX7 expression and cardiogenesis has been previously examined (Nelson, Chiriac et al 2009). SOX family transcription factors have been implicated in the regulation of cardiac and/or vascular fate selection during early embryonic development (Naito, Shiojima et al 2006;Nelson, Chiriac et al 2009).…”

“…SOX family transcription factors have been implicated in the regulation of cardiac and/or vascular fate selection during early embryonic development (Naito, Shiojima et al 2006;Nelson, Chiriac et al 2009). Bioinformatics analysis has revealed that the Wnt/β-catenin signaling pathway, which has been demonstrated to drive early progenitor cells into mature cardiomyocytes, is a target of SOX transcription factors (Faustino, Behfar et al 2008).…”

“…Bioinformatics analysis has revealed that the Wnt/β-catenin signaling pathway, which has been demonstrated to drive early progenitor cells into mature cardiomyocytes, is a target of SOX transcription factors (Faustino, Behfar et al 2008). Differential SOX7 expression has been associated with cardiovascular lineage specification in Flk-1 + PS-like cells (Nelson, Chiriac et al 2009). It has also been reported that SOX7 can inhibit the Wnt/β-catenin pathway (Takash, Canizares et al 2001), which as discussed in Chapter 1, is involved in commitment of mesoderm towards the vascular and hematopoietic lineages but inhibits cardiac induction (Naito, Shiojima et al 2006).…”

Sox7 in vascular development: review, insights and potential mechanisms

“…SOX7 has been proposed as a potent activator in the endothelial differentiation of Flk-1 + cells (Yamauchi et al, 2007). Importantly, in the Flk1 + population, the vasculogenic Sox7 transcription factor is significantly up-regulated, overlapping with the emergence of the cardiac transcription factors Nkx2.5 and Gata4 (Nelson et al, 2009). Notably, sorting the parental Flk-1 + pool using the CXCR4/ Flk-1 biomarker pair, which is a predictor of the beginning of heart cell specification among pluripotent stem cells, reveals a divergent Sox7 expression, with significantly lower Sox7 expression in the cardiogenic subpopulation compared with the subpopulation enriched for endothelial and smooth muscle markers of vasculogenesis (Nelson et al, 2009).…”

“…Notably, sorting the parental Flk-1 + pool using the CXCR4/ Flk-1 biomarker pair, which is a predictor of the beginning of heart cell specification among pluripotent stem cells, reveals a divergent Sox7 expression, with significantly lower Sox7 expression in the cardiogenic subpopulation compared with the subpopulation enriched for endothelial and smooth muscle markers of vasculogenesis (Nelson et al, 2009). Thus, differential Sox7 expression may be a potential regulatory switch in deciding between cardiac and vascular pathways in Flk1 + multi-lineage precursors (Nelson et al, 2009). Wnt/b-catenin appears to be a key signaling cascade that integrates the SoxF family, including Sox7, with the cardiovascular VEGF/Flk-1 and SDF1/CXCR4 pathways (Nelson et al, 2009).…”