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Background  Thrombospondin-1 (TSP-1), a Ca 2+ -binding trimeric glycoprotein secreted by multiple cell types, has been implicated in the pathophysiology of several clinical conditions. Signaling involving TSP-1, through its cognate receptor CD47, orchestrates a wide array of cellular functions including cytoskeletal organization, migration, cell-cell interaction, cell proliferation, autophagy, and apoptosis. In the present study, we investigated the impact of TSP-1/CD47 signaling on Ca 2+  dynamics, survival, and deformability of human red blood cells (RBCs).    Methods  Whole-cell patch-clamp was employed to examine transmembrane cation conductance. RBC intracellular Ca 2+  levels and multiple indices of RBC cell death were determined using cytofluorometry analysis. RBC morphology and microvesiculation were examined using imaging flow cytometry. RBC deformability was measured using laser-assisted optical rotational cell analyzer.    Results  Exposure of RBCs to recombinant human TSP-1 significantly increased RBC intracellular Ca 2+  levels. As judged by electrophysiology experiments, TSP-1 treatment elicited an amiloride-sensitive inward current alluding to a possible Ca 2+  influx via non-selective cation channels. Exogenous TSP-1 promoted microparticle shedding as well as enhancing Ca 2+ - and nitric oxide-mediated RBC cell death. Monoclonal (mouse IgG1) antibody-mediated CD47 ligation using 1F7 recapitulated the cell death-inducing effects of TSP-1. Furthermore, TSP-1 treatment altered RBC cell shape and stiffness (maximum elongation index).    Conclusions  Taken together, our data unravel a new role for TSP-1/CD47 signaling in mediating Ca 2+  influx into RBCs, a mechanism potentially contributing to their dysfunction in a variety of systemic diseases.Video abstract

Thrombospondin-1/CD47 signaling modulates transmembrane cation conductance, survival, and deformability of human red blood cells