CD34 orchestrates the formation and actions of microvilli for efficient E-selectin-mediated cell migration

Abstract Hematopoietic stem/progenitor cells (HSPCs) exit the blood stream and migrate to the bone marrow by extending their microvilli into tethers, in response to shear-resistant binding between ligands on HSPCs and E- and/or P-selectin, on the endothelial cell layer. Several selectin ligands have been identified; however, their mechanisms in microvilli formation and extension into tethers remain elusive. Using several super-resolution imaging techniques and functional assays, we showed that CD34 orchestrates these mechanisms. CD34 is indispensable for microvilli formation, enhancing tether formation by increasing its clustering and adopting a unique ring-like localization pattern at the microvillus tip, which can encapsulate other ligands, forming a dense tethering site for E-selectin. CD34 transduces E-selectin binding by phosphorylating the ERM protein ezrin, enhancing microvilli and tether formation in vitro and cell migration in vivo. Thus, CD34 plays a key role in the mechanical and signaling mechanisms of the microvilli, during cellular tethering and rolling.