State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, China.
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, China; Faculty of Laboratory Medical Science, Hebei North University, Zhangjiakou, China.
Biol Blood Marrow Transplant. 2018 Jun;24(6):1142-1151. doi: 10.1016/j.bbmt.2018.01.027. Epub 2018 Feb 1.
Prolonged isolated thrombocytopenia (PT) is a severe complication in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether the megakaryoctic potential of hematopoietic stem cells (HSCs) in bone marrow is intact and what factors drive the pathological process of PT remain elusive. A retrospective study in patients (n = 285) receiving HSCT revealed that the occurrence of PT was approximately 8% and the number of platelets and megakaryocytes in PT patients is much lower compared with control subjects. To test whether the deficiency of thrombopoiesis was caused by the activities of HSCs, the megakaryocytic differentiation potential of HSCs before or after transplantation was assessed. Interestingly, a substantial decrease of megakaryocytic differentiation was observed 2 weeks after transplantation of HSCs in all of the allo-HSCT recipients. However, 4 weeks after transplantation, the ability of HSCs to generate CD41CD42b megakaryocytes in successful platelet engraftment patients recovered to the same level as those of HSCs before implantation. In contrast, HSCs derived from PT patients throughout the postimplantation period exhibited poor survival and failed to differentiate properly. A protein array analysis demonstrated that multiple inflammation-associated cytokines were elevated in allo-HSCT recipients with PT. Among them, insulin-like growth factor-binding protein 1 and regulated on activation, normal T cell expressed and secreted were found to significantly suppress the proliferation and megakaryocytic differentiation of HSCs in vitro. Our results suggested that the occurrence of PT may be attributed, at least partially, to the damage to HSC function caused by inflammation-associated cytokines after HSCT. These findings shed light on the mechanism underlying HSC megakaryocytic differentiation in PT patients and may provide potential new strategies for treating PT patients after HSCT.
孤立性血小板减少症（PT）是异基因造血干细胞移植（allo-HSCT）后患者的一种严重并发症。骨髓造血干细胞（HSCs）的巨核细胞生成潜能是否完整，以及哪些因素驱动 PT 的病理过程，目前仍不清楚。一项对接受 HSCT 的患者（n=285）的回顾性研究显示，PT 的发生率约为 8%，PT 患者的血小板和巨核细胞数量明显低于对照组。为了测试血小板生成缺陷是否是由 HSCs 的活性引起的，评估了移植前后 HSCs 的巨核细胞分化潜能。有趣的是，在所有 allo-HSCT 受者中，移植后 2 周观察到 HSCs 的巨核细胞分化明显减少。然而，移植后 4 周，成功血小板植入患者的 HSCs 生成 CD41CD42b 巨核细胞的能力恢复到与植入前相同的水平。相比之下，PT 患者的 HSCs 在整个植入后时期表现出较差的生存能力和未能正常分化。蛋白质阵列分析表明，PT 患者的 allo-HSCT 受者中多种炎症相关细胞因子升高。其中，胰岛素样生长因子结合蛋白 1 和活化调节正常 T 细胞表达和分泌因子被发现可显著抑制 HSCs 的增殖和巨核细胞分化。我们的结果表明，PT 的发生至少部分归因于 HSCT 后炎症相关细胞因子对 HSC 功能的损害。这些发现揭示了 PT 患者 HSC 巨核细胞分化的机制，并可能为 HSCT 后 PT 患者的治疗提供潜在的新策略。
