Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China; and.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Blood. 2016 Dec 22;128(25):2988-2999. doi: 10.1182/blood-2016-03-702803. Epub 2016 Oct 21.
Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells in the bone marrow (BM) microenvironment. Our previous work found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. In the current study, we evaluated the function of BM EPCs in subjects with PGF postallotransplant. Moreover, we investigated whether atorvastatin could enhance the number and function of BM EPCs derived from subjects with PGF in vitro. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cyclic adenosine monophosphate-responsive element-binding protein were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through downregulation of the p38 MAPK pathway. In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through downregulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF postallotransplant.
移植物功能不良（PGF）是异基因造血干细胞移植（allo-HSCT）后的一种严重并发症。 鼠类研究表明，内皮祖细胞（EPCs）是骨髓（BM）微环境中造血干细胞的首选支持细胞。 我们之前的工作发现，BM EPC 数量减少是 allo-HSCT 后 PGF 发生的独立危险因素。 然而，对于 BM EPC 的功能作用以及如何改善 PGF 中受损的 BM EPC 知之甚少。 在本研究中，我们评估了 PGF 患者 BM EPC 的功能。 此外，我们还研究了阿托伐他汀是否可以在体外增强 PGF 患者来源的 BM EPC 的数量和功能。 在 PGF 患者中，发现 BM EPC 表现出增殖、迁移、血管生成受损，活性氧和细胞凋亡水平升高，功能失调。 在 PGF 患者的 BM EPC 中检测到 p38 及其下游转录因子环磷酸腺苷反应元件结合蛋白的激活。 此外，通过下调 p38 MAPK 通路，阿托伐他汀在体外处理可增强 PGF 患者来源的 BM EPC 的数量和功能。 综上所述，在 PGF 患者中观察到功能失调的 BM EPC。 阿托伐他汀在体外通过下调 p38 MAPK 通路可定量和功能改善 PGF 患者来源的 BM EPC。 这些数据表明，阿托伐他汀代表了一种有前途的治疗方法，可用于修复 allo-HSCT 后 PGF 患者受损的 BM EPC。
