SEMA4D-heparin Complexes Immobilized on Titanium Surfaces Have Anticoagulant, Cell-Migration-Promoting, and Immunoregulatory Effects

Soluble semaphorin 4D (SEMA4D) is a 120 kDa transmembrane protein, which belongs to the semaphorin family of axon guidance molecules that act primarily axonal repellents. SEMA4D elicits its migration-promoting and immunomodulatory effects through activation of PLXNB1 and CD72, respectively. In this study, SEMA4D combined with heparin were adsorbed onto cationic surfaces. The biocompatibility evaluation results indicated that the SEMA4D-heparin-modified surfaces displayed less platelet adhesion and activation, prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) and reduced fibrinogen gamma chain (FGG) exposure and fibrinogen adhesion. Additionally, endothelial cells (ECs) showed improved adhesion density and proliferation activity on the SEMA4D-heparin-modified surfaces. Chemotactic and haptotaxis assays indicated a highly guided migration for ECs on the modified surfaces. The immunological tests revealed that the SEMA4D-heparin complexes had a positive immunomodulatory effect on macrophages and promoted macrophages polarization into M2 phenotypes. Overall, the results suggested that the SEMA4D-heparin complexes can be a potential therapeutic agent to promote tissue healing and accelerate in situ endothelialization with minimal side effects and positive immunomodulatory effect.