Circulating Wnt Ligands Activate the Wnt Signaling Pathway in Mature Erythrocytes

Abstract

Objective: The deformation ability of erythrocytes is critical for their function and affects their mobility in the circulation. To circulate and travel through narrow vessels, erythrocytes must continuously alter their shape by modifying their cytoskeleton, which controls their elasticity and stability. Erythrocytes lack nuclei and other major organelles, and thus most of the known signaling cascades are thought to be inactive in these cells. As the noncanonical Wnt pathway affects cytoskeleton dynamics by posttranslational modifications, we hypothesized that this signaling pathway may affect erythrocytes. Approach and Results: We demonstrate that components of the noncanonical Wnt pathway are expressed in erythrocytes and that incubation of erythrocytes with Wnt ligands prolonged their survival both ex vivo, under storage conditions, and in posttransfusion recipient mice. We show that Wnt ligands modulate the erythrocyte cytoskeleton, enhancing its flexibility and strength. Importantly, we show that the noncanonical Wnt-5A ligand is secreted into the plasma and that monocytes and lymphocytes are a possible source of the Wnt effectors in the blood circulation. Conclusions: These findings provide evidence for intracellular signaling activity in enucleated cells and signal transduction in the blood circulation and thus open new and exciting avenues for studying the function of signaling pathways in the bloodstream.