电离辐射诱导巨核细胞损伤对造血干细胞稳态的影响作用与机制研究

骨髓是放射损伤的主要靶器官，骨髓重度放射损伤后常会因为造血干细胞（HSCs）枯竭而引起造血功能衰竭，但其发生机制尚远未阐明。新近研究发现，骨髓HSCs的后代细胞—巨核细胞具有逆向调控HSCs稳态的作用。已知，巨核系造血功能障碍是骨髓放射损伤的一个主要病理改变，也是影响放射损伤患者病情发展与转归的重要因素。因此，我们推测电离辐射可能会通过损伤巨核细胞而导致骨髓HSCs稳态失衡，进而引发或加重HSCs枯竭和造血功能衰竭。基于此，本研究拟采用白喉毒素诱导巨核细胞条件性敲除小鼠，首先明确轻、中度放射损伤后巨核细胞在HSCs稳态调节和造血功能恢复中的作用，进而深入探讨重度放射损伤对骨髓巨核祖细胞存活和成熟巨核细胞分泌相关细胞因子能力的影响及作用机制，并分析巨核细胞放射损伤与骨髓HSCs稳态失衡发生的关系，以进一步揭示骨髓放射损伤后HSCs枯竭和造血功能衰竭的发生机理，并为其救治探寻新的、有效途径。

Bone marrow is the main target organ of radiation injury. Severe radiation injury often leads to bone marrow failure because of the exhaustion of hematopoietic stem cells (HSCs). However, its mechanism is still far from to clarify. Recent studies have found that megakaryocytes which are the offspring of HSCs can reversely regulate the homeostasis of HSCs. As known, megakaryocytes dysfunction is not only one of the main pathological changes of bone marrow induced by radiation, but also an important factor affecting the progression and outcome of patients with radiation injury. Therefore, we presume that ionizing radiation can cause the imbalance of HSCs homeostasis through injuring megakaryocytes, thereby triggering or aggravating HSCs exhaustion and bone marrow failure. Based on this, in this study, by adopting diphtheria toxin induced megakaryocyte conditional knock-out mice, we will firstly reveal the function of megakaryocytes in the regulation of HSCs homeostasis and hematopoiesis recovery after light or moderate radiation injury. Then we plan to explore the influence and underlying mechanism of severe radiation on the survival of megakaryoblast cells and the ability of mature megakaryocytes to secrete certain cytokines, including TGF-β1, PF4 and FGF1. The aim of this study is to uncover the mechanism of HSCs exhaustion and bone marrow failure after radiation and to search for a new and effective approach for its clinical treatment.