TGF-β通路介导的骨髓血管内皮细胞损伤在移植后造血重建不良中的作用及其调控机制

移植后造血重建不良（PHR，包括植入功能不良和血小板延迟植入）是导致移植失败的重要原因之一。近年来，本课题组围绕PHR开展了系列转化研究，率先揭示骨髓血管内皮细胞（EC）损伤所致造血干细胞异常是导致PHR的重要原因，制定修复骨髓EC促进造血的治疗新策略，部分改善了PHR临床疗效。但是，PHR患者骨髓EC损伤，特别是其造血支持能力受损的分子机制仍是亟待解决的重要科学问题。转化生长因子（TGF-β）具有多效调控EC的作用，但TGF-β在PHR患者骨髓EC损伤中的作用及其调控机制尚待阐明。近期预实验提示，TGF-β通路异常激活所致骨髓EC损伤及其造血支持能力下降可能是导致PHR的新机制。因此，在前期工作基础上，本课题拟联合利用临床队列-动物模型-体外实验-组学分析，从“TGF-β如何调控骨髓EC”这一崭新视角，探讨移植后PHR的发病机制及其治疗新策略，从而促进移植后造血重建，提高移植疗效。

Although most patients achieve rapid and stable hematopoietic recovery after allogeneic hematopoietic stem cell transplantation(allo-HSCT), poor hematopoietic reconstitution(PHR), including poor graft function and prolonged isolated thrombocytopenia, remains a life-threatening complication and contributes to high morbidity and mortality after allo-HSCT. Due to the limited mechanistic studies, the clinical management of PHR is challenging. Therefore, a better understanding of the pathogenesis of PHR will help guide effective treatment and eventually improve prognosis. In recent years, the applicant has been focusing on the translational research in PHR. Our series studies demonstrated that the dysfunctional bone marrow(BM) endothelial cells(ECs) hampered the hematopoietic reconstitution of the successfully engrafted donor hematopoietic stem cells(HSCs), ultimately leading to the occurrence of PHR after allo-HSCT. We recently reported that N-acetyl-L-cysteine(NAC), a ROS scavenger, could enhance defective HSCs by repairing dysfunctional BM ECs of PHR patients. Moreover, prophylactic oral NAC reduced PHR by improving BM ECs after allo-HSCT. However, little is known regarding the underlying regulatory mechanism of the dysfunctional ECs, especially the impaired HSC-supporting ability of ECs in PHR patients. Accumulating evidences have demonstrated the essential roles of BM ECs in supporting HSCs and of transforming growth factor-β(TGF-β) signaling in regulating diverse functions of ECs, raising the question of whether TGF-β signaling in ECs plays a critical role in supporting HSCs. Moreover, it is unknown whether the aberrant TGF-β signaling in ECs and their impaired HSC-supporting ability is involved in the pathogenesis of PHR after allo-HSCT. More recently, our preliminary experiments showed the aberrant activated TGF-β signaling in BM ECs of PHR patients. Although requiring further validation, our preliminary results suggest that the dysfunctional BM ECs regulated by the activated TGF-β signaling may play an important role in the pathogenesis of PHR, which provides a promising therapeutic approach for PHR patients. Based on our previous work and recent preliminary experiments, the current study attempts to investigate the effect of the impaired BM ECs regulated by TGF-β signaling on the hematopoietic reconstitution in patients after allo-HSCT. Furthermore, the underlying mechanism and its therapeutic potential will be investigated in a prospective case-control study, conditionally genetically engineered mice model, in vitro study and RNA sequencing analysis. Taken together, improvement of BM ECs regulated by TGF-β signaling may be a promising therapeutic approach to promote hematopoietic reconstitution and eventually improve the clinical prognosis of patients after allo-HSCT in the future.