Abstract 17509: Lysophosphatidic Acid Activates Bone Marrow Mesenchymal Stromal Cells and Augments the Heterotypical Interactions with Endothelial Cells
Introduction: Lysophosphatidic acid (LPA) is a bioactive lipids that play a key role in vascular development and angiogenesis. LPA is also a potent regulator of endothelial cell (EC) activation and function, but its effects on supporting cells (SCs) are not know. We hypothesized that LPA may also promote SC activation which, when combined with the heterotypic interactions between SCs and ECs in 3D aggregates, would lead to robust in vitro angiogenesis that could be harnessed for future vascularization of engineered tissues.
Methods: Aggregates of human umbilical vein ECs (HUVECs), human bone marrow mesenchymal stromal cells (MSCs) and the combination of both were generated by hanging drop culture. Cellular aggregates were then implanted into fibrin that was modified by the addition of 2 mM LPA. After 24 hours, aggregates were assessed for sprout length and branch number. VEGF, FGF and PDGF production were measured. Activation of signaling cascades were assessed by measuring the phosphorylation of FGF-receptor, MAPK, MEK and JNK.
Results: While the combination of MSCs + HUVECs in 3D aggregates resulted in an improvement in sprout length/branching as compared to HUVECs alone, the addition of LPA resulted in a 5x increase in sprout length/branching for both cell types (p<0.01). LPA doubled FGF production in both cell types (p<0.01), but did not affect VEGF or PDFG production which was both increased by MSC and HUVEC interaction (Fig). As expected, FGF receptor activation and downstream signal transduction cascade was increased by LPA in aggregates of HUVECs, MSCs and the combination of both.
Conclusion: LPA activates both HUVECs and MSCs to promote tubule formation and augments the cellular interactions of HUVECs and MSCs leading to an increase in vitro angiogenesis. LPA activation of both HUVECs and MSCs are FGF-mediated and are distinct from those derived from heterotypic cellular interactions. These findings suggest a novel mechanism of LPA-induced angiogenesis.
- © 2012 by American Heart Association, Inc.