Blockade of TSP-1/CD47 signal axis promotes donor hematopoietic engraftment by improving SEC/MK niche function
Feng Wang1,2, Yan-Hou Liu1,2, Ting Zhang1,2
1Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, China.
Abstract:
Thrombospondin-1 (TSP-1)/CD47 signaling induces cell death and inhibits 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 hematopoietic stem cell transplantation (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 to enhance HSCT efficacy and reduce endothelial injury syndrome.
Insights
Blocking the Thrombospondin-1 (TSP-1)/CD47 pathway improves hematopoietic stem cell transplantation (HSCT) engraftment. This strategy enhances donor stem cell homing and bone marrow vascular regeneration, offering a promising therapeutic target.
Area of Science:
- Hematology
- Immunology
- Regenerative Medicine
Background:
- Thrombospondin-1 (TSP-1) and CD47 signaling inhibit angiogenesis and promote cell death.
- Hematopoietic stem cell transplantation (HSCT) is a critical therapy, but donor engraftment can be limited.
- Understanding pathways that regulate stem cell homing and niche support is crucial for improving HSCT outcomes.
Purpose of the Study:
- To investigate the therapeutic potential of blocking the TSP-1/CD47 pathway to enhance donor engraftment in HSCT.
- To elucidate the mechanisms by which TSP-1/CD47 signaling affects hematopoietic stem cell (HSC) homing and bone marrow (BM) vascular regeneration.
Main Methods:
- Utilized mouse models of total body irradiation (TBI)-conditioned syngeneic HSCT.
- Compared HSCT outcomes in wild-type (WT) mice with those deficient in CD47 (Cd47-/-) or TSP-1 (Thbs1-/-).
- Administered anti-TSP-1 antibody in WT mice to assess therapeutic efficacy.
Main Results:
- Mice lacking CD47 or TSP-1 exhibited significantly improved HSCT engraftment compared to WT mice.
- Absence of TSP-1 or CD47 led to increased CXCL12 production, enhancing donor HSC homing to specific bone marrow niches.
- Deficiency in TSP-1/CD47 reduced platelet adhesion, attenuated endothelial injury, and promoted BM vascular regeneration, preserving sinusoidal endothelial cell (SEC) niches.
Conclusions:
- The TSP-1/CD47 pathway negatively regulates donor HSC engraftment and BM vascular niche integrity.
- Blocking TSP-1/CD47 signaling enhances HSC homing and promotes vascular regeneration post-HSCT.
- Targeting the TSP-1/CD47 pathway represents a promising strategy to improve HSCT efficacy and mitigate endothelial injury.
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