The role of a soluble, competitive FGF receptor in embryonic stem cell-derived hematopoiesis

Abstract

The fibroblast growth factor (FGF) signaling pathway plays a pivotal role in the maintenance of embryonic stem cells (ESCs) as well as their differentiation into the hematopoietic lineage. We observed that supplementing human and rhesus ESCs in embryoid body (EB) culture with the FGF-2 ligand showed a dose-dependent stimulation of hematopoietic differentiation. However, despite phylogenetic similarities, rhesus ESCs needed a 5-fold greater concentration of FGF-2 relative to human ESCs to achieve optimal hematopoiesis. To elucidate the mechanism behind this species-specific differential requirement for the central growth factor FGF-2, we measured and compared endogenous gene expression of FGF ligands and splice variant isoforms of FGF receptor 1 (FGFRI) between human and rhesus ESC lines. The results indicate that rather than an inherent lack of FGF ligand production in rhesus ESCs relative to human ESCs, there are significant differences in their expression of FGFRI isoforms. Our findings suggest that an increasing fraction of the soluble, competitive inhibitor sFGFRI isoform relative to the functional FGFRlα isoform expressed in ESC cultures correlates (r2=0.84) to a decrease in the degree of hematopoietic differentiation achieved by a differentiating ESC population. This finding not only offers an explanation for the observed differences between rhesus and human hematopoiesis, but also implies a mechanism by which developing cells can self-regulate hematopoietic induction by secretion of competitive, inhibitory receptor isoforms.