骨髓血管内皮细胞糖代谢异常在移植后植入功能不良中的作用机制及其修复研究

With the increasing application of allogeneic hematopoietic stem cell transplantation (allo-HSCT), poor graft function (PGF) has emerged as a growing obstacle, contributing to high morbidity and mortality after allo-HSCT. However, the pathogenesis of PGF remains poorly understood, and the clinical management is challenging. In the past 5 years, the applicant has been making her continuous efforts to elucidate the pathogenesis and establish the novel treatment strategies for PGF after allo-HSCT. She recently reported that the reduced and dysfunctional bone marrow endothelial progenitor cells (EPCs) hampered the hematopoietic reconstitution of the successfully engrafted donor hematopoietic stem cells, ultimately leading to the occurrence of PGF after allo-HSCT. Meanwhile, high levels of reactive oxygen species (ROS) play important roles in the impairment and recovery of bone marrow EPCs in PGF patients (Blood. 2016). However, little is known regarding the underlying regulatory mechanism of the aberrant ROS levels and dysfunction of bone marrow EPCs in PGF patients. More recently, our preliminary data showed the aberrant glycolysis and pentose phosphate pathway, the increased levels of ROS, and the reduced levels of peroxisome proliferator-activated receptor delta (PPARδ) in bone marrow EPCs of PGF patients. Moreover, our in vitro study demonstrated that the inhibition of PPARδ contributed to the aberrant glycolysis and pentose phosphate pathway, and the increased levels of ROS. Although requiring further validation, the above preliminary results indicate that the PPARδ inhibition-mediated aberrant glucose metabolism of the bone marrow EPCs may play important roles in the pathogenesis of PGF, which promises to be a novel treatment target in PGF patients. Based on our previous work and preliminary experiments, the current study attempts to investigate whether the aberrant glucose metabolism is involved in the impairment of bone marrow EPCs in PGF patients. Furthermore, the underlying mechanism of the above observation and its therapeutic potential will be investigated in a prospective case-control study, in vitro study and multi-omics analysis. Therefore, the successful implementation of the translational studies may provide novel therapeutic strategies, and it may eventually improve the clinical outcomes of PGF patients post-allotransplant in the future.

植入功能不良（PGF）是随着异基因造血干细胞移植广泛应用出现的新的移植并发症，尚无有效防治手段，是亟待解决的重要临床科学问题。近年来，申请人围绕PGF的发病机制开展了系列研究，发现骨髓血管内皮细胞（EPCs）异常所致造血干细胞损伤参与了PGF的发生，而活性氧增多在骨髓EPCs的损伤与修复中发挥着重要作用（Blood.2016）。但是，PGF患者活性氧增多、骨髓EPCs损伤的机制及其修复策略尚不明确。近期预实验提示，PPARδ表达降低所致糖酵解、磷酸戊糖途径异常，可能是导致PGF患者活性氧增多、骨髓EPCs损伤的重要原因，并有望成为PGF患者新的治疗靶点。在前期工作基础上，本研究旨在通过前瞻性临床病例配对研究、体外实验和多组学分析，在骨髓EPCs和造血干细胞水平，深入探讨与PGF发病相关的骨髓EPCs糖代谢异常及其靶向治疗，揭示其潜在的分子机制，从而为PGF患者提供新的防治策略、改善预后。

植入功能不良（PGF）是随着异基因造血干细胞移植广泛应用出现的新的移植并发症，尚无有效防治手段，是亟待解决的重要临床科学问题。近年来，申请人围绕PGF的发病机制开展了系列研究，发现骨髓血管内皮细胞（EPC）异常所致造血干细胞损伤参与了PGF的发生，而糖代谢异常导致活性氧增多在植入功能不良患者骨髓EPC的损伤与修复中发挥着重要作用。但是，PGF患者活性氧增多、骨髓EPC损伤的机制及其修复策略尚不明确。在前期工作基础上，本研究旨在通过前瞻性临床病例配对研究、体外实验和多组学分析，在骨髓EPC和造血干细胞水平，深入探讨与PGF发病相关的骨髓EPC糖代谢异常及其靶向治疗，揭示其潜在的分子机制，从而为PGF患者提供新的防治策略。.本项目重要研究成果包括：①揭示糖酵解异常是骨髓EPC损伤及其造血支持能力下降的新机制，为化疗、放疗和造血干细胞移植等治疗后造血重建不良患者基于发病机制的精准治疗策略的建立提供了潜在新靶点；②发现细胞能量代谢调控因子PPARδ异常参与骨髓EPC损伤、导致其造血支持能力下降；③揭示骨髓M1和M2两种巨噬细胞亚型对巨核细胞具有相反的调控作用，M2巨噬细胞通过激活PI3K-AKT通路对巨核细胞发挥支持作用，为血小板减少症患者提供了潜在的治疗新靶点；④通过随机对照III期临床试验证实，预防性NAC通过改善骨髓EPC有效促进了异基因造血干细胞移植后造血重建；⑤在项目执行期内，项目负责人作为第一作者/通讯作者（含共同）在Haematologica、STTT等杂志共发表标注本项目编号的SCI论文11篇；在美国血液学年会、欧洲血液学年会等本领域最高水平国际学术会议上特邀报告2次、大会发言10次、墙报交流6次、获得美国血液学年会“ASH Abstract Achievement Award”2次；获得4项国家发明专利授权；获得2项科研奖励；培养博士研究生3名和硕士研究生2名。.总之，本项目为从骨髓血管内皮细胞糖代谢异常的视角理解异基因造血干细胞移植后的植入功能不良患者的发病机制，并为制定有效防治植入功能不良的治疗新策略提供了理论依据，具有重要的临床转化应用价值。