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.

Inflammation and atherosclerosis: signaling pathways and therapeutic intervention

“…A more recent study characterized a novel role of Wnt signaling in enucleated erythrocytes and uncovered that regulation of the red blood cell (RBC) cytoskeleton and erythrocyte survival was controlled by noncanonical Wnt signals. 278 Treatment of erythrocytes with Wnt5 increased RBC survival and improved oxygen delivery while maintaining normal cell morphology. 278 The ability of the Wnt pathway to increase RBC flexibility may prove essential in combatting hypoxia by ensuring that RBCs better traverse occluded and inflamed vessels and capillaries.…”

“… 278 Treatment of erythrocytes with Wnt5 increased RBC survival and improved oxygen delivery while maintaining normal cell morphology. 278 The ability of the Wnt pathway to increase RBC flexibility may prove essential in combatting hypoxia by ensuring that RBCs better traverse occluded and inflamed vessels and capillaries. Perhaps increased oxygen delivery through improved erythrocyte health may slow the development of unstable plaque formation or thrombotic release and reduce the risk of myocardial infarction or stroke in patients with advanced atherosclerosis.…”

Exploring the Clinical Implications of Wnt Signaling in Enucleated Erythrocytes

“…Siman-Tov et al 7 hypothesized that treatment of erythrocytes with Wnt ligands would improve RBC survival while allowing for the maintenance of an adaptable morphology. Indeed, erythrocytes have been previously shown to contain JNK (c-Jun N-terminal kinase), Rac1 (Ras-related C3 botulinum toxic substrate 1), RhoA (Ras homolog family member A), and PKC (protein kinase C), all integral components associated with the noncanonical Wnt pathway.…”

“…[1][2][3] The developmental role of Wnt signaling has been characterized primarily in stem and progenitor cell populations and is associated with canonical β-catenin mediated transcriptional regulation in nucleated cells. 2,[4][5][6] In this volume of ATVB, Siman-Tov et al 7 characterized a novel role of Wnt signaling in enucleated erythrocytes and uncovered that regulation of the red blood cell (RBC) cytoskeleton and erythrocyte survival was controlled by noncanonical Wnt signals. 7 Erythrocytes undergo tremendous strain when traveling through pressurized capillaries where gas exchange with tissues can occur.…”

Therapeutic approaches to activate the canonical Wnt pathway for bone regeneration

“…There are a total of 19 Wnt ligands (secreted glycoproteins which activate Wnt) which target 10 different receptors in the frizzled (Fzd) protein family with multiple co‐receptors required to activate a downstream response (Liu et al., 2013 ; Siman‐Tov et al., 2021 ). Each Wnt ligand may stimulate different Wnt pathways depending on the receptor and co‐receptor combination, yet there are several ligands strongly associated with canonical Wnt (Wnt1, Wnt3a) (Liu et al., 2013 ; Siman‐Tov et al., 2021 ). Wnt ligands undergo extensive post translational modifications with one of the most significant modifications to these proteins being lipidation.…”