Blockade of TSP-1/CD47 signal axis promotes donor hematopoietic engraftment by improving SEC/MK niche function
Description
Thrombospondin-1 (TSP-1)/CD47 signaling has been shown to induce cell death and inhibit angiogenesis. Here we investigated the possibility of improving donor engraftment by blocking the TSP-1/CD47 pathway in mouse models of total body irradiation (TBI)-conditioned syngeneic HSCT. Our findings revealed that HSCT engraftment was improved in mice deficient in CD47 (Cd47−/−) or TSP-1 (Thbs1−/−) compared to wild-type (WT) mice. The lack of TSP-1 or CD47 enhanced the production of CXCL12 by megakaryocytes and platelets, promoting the seeding of donor hematopoietic stem cells (HSCs) in sinusoidal endothelial cell (SEC)/megakaryocyte niches. Both Cd47−/− and Thbs1−/− mice showed reduced platelet adhesion to sinusoidal vascular cells, attenuated endothelial injury, and enhanced BM vascular regeneration, preserving SEC niches. Antibody neutralization of TSP-1 significantly increased CXCL12 production, donor HSC engraftment, and vascular niche regeneration in WT mice. In summary, the TSP-1/CD47 pathway is a promising therapeutic target for enhancing HSCT efficacy and ameliorating HSCT-related endothelial injury syndrome.