Wang Feng, Liu Yan-Hou, Zhang Ting, Hou Xintong, Xin Yanbao, Xie Guang-Yao, Zhao Wen-Jie, Wang Xue, Sun Tianmeng, Hu Zheng, Yang Yong-Guang
Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, China.
National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China.
iScience. 2025 Feb 4;28(3):111952. doi: 10.1016/j.isci.2025.111952. eCollection 2025 Mar 21.
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 ( ) or TSP-1 ( ) 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 and 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.
血小板反应蛋白-1（TSP-1）/CD47信号传导诱导细胞死亡并抑制血管生成。在此，我们在全身照射（TBI）预处理的同基因造血干细胞移植（HSCT）小鼠模型中研究了通过阻断TSP-1/CD47途径来改善供体植入的可能性。我们的研究结果显示，与野生型（WT）小鼠相比，CD47缺陷（ ）或TSP-1缺陷（ ）小鼠的HSCT植入得到改善。TSP-1或CD47的缺失增强了巨核细胞和血小板产生CXCL12的能力，促进供体造血干细胞（HSC）在窦状内皮细胞（SEC）/巨核细胞龛中的定植。 和 小鼠均表现出血小板与窦状血管细胞的黏附减少、内皮损伤减轻以及骨髓血管再生增强，从而保留了SEC龛。对WT小鼠进行TSP-1抗体中和可显著增加CXCL12的产生、供体HSC植入以及血管龛再生。总之，TSP-1/CD47途径是提高HSCT疗效和减少内皮损伤综合征的一个有前景的治疗靶点。
