SDF-1/CXCR4在急性髓系白血病骨髓间充质干细胞胞内转运机制

Chemokine stromal-derived factor-1 (SDF-1) and its receptor CXCR4 play an important role in the migration and homing of the transplanted hematopoietic stem cells (HSCs). Bone marrow-derived mesenchymal stem cells (BM-MSCs) express these molecules. Our studies have shown that SDF-1 level in bone marrow plasma from patients with acute myeloid leukemia (AML) was reduced. Co-infusion of healthy MSCs increased the level of SDF-1 in the peripheral blood of patients with AML and improved hematopoietic stem cells (HSCs) engraftment after transplantation. In addition, expression of both CXCR4 and SDF-1 was found to be increased, but excessively retained in the BM-MSCs in AML. Based on these findings, we propose the following hypothesis to be tested in this study: 1. The abnormal intracellular trafficking of SDF-1/CXCR4 results in its excessive storage (retention) in BM-MSCs of AML; 2. Impaired protein post-translational modification may contribute to abnormal intracellular trafficking of SDF-1/CXCR4; 3. Certain chemotherapeutic agents through screening may help reverse the abnormal intracellular trafficking of SDF-1/CXCR in AML. Taken together, this study will improve our understanding in the molecular mechanisms of how AML alters intracellular trafficking of SDF-1/CXCR4 in human bone marrow MSCs. Results from this study may provide therapeutic implications in hematopoietic stem cells transplantation as a treatment of AML.

基质细胞衍生因子-1（SDF-1）及其受体CXCR4在移植后造血干细胞的迁移及归巢过程中起了重要作用，骨髓间充质干细胞（BM-MSCs）表达这些分子。前期实验发现SDF-1水平在急性髓系白血病（AML）骨髓血浆中下降，输注健康人BM-MSCs能改善这一缺损并促进造血植入。相反，SDF-1/ CXCR4在AML患者BM-MSCs胞内过量滞留。这些新发现使我们形成以下设想，并在本项目进行验证：1.SDF-1/CXCR4在AML患者BM-MSCs胞内运输异常，而致胞内异常储积; 2. 蛋白质翻译后修饰（如糖基化）异常可能是导致SDF-1/CXCR4细胞内转运异常的机制之一; 3. 筛选出特定的化疗药物，有助于纠正SDF-1/CXCR4在BM-MSCs胞内异常运输。本研究旨在揭示AML疾病本身导致BM-MSCs细胞内SDF-1/CXCR4表达异常的分子机制以及逆转这种异常在造血干细胞移植中的作用。

基质细胞衍生因子-1（SDF-1）及其受体CXCR4在造血干细胞迁移及归巢过程的重要作用已经得到广为研究。本研究旨在探讨急性髓系白血病(AML)对CXCR4在骨髓间充质干细胞(BM-MSCs)胞内的分布及表达的影响。我们利用免疫荧光共聚焦的方法观察CXCR4的亚细胞器定位以及在细胞膜上的分布，首次从亚细胞水平发现CXCR4在AML患者BM-MSCs表达分布异常，这种表达改变能被化疗逆转。在对BM-MSCs细胞功能的研究中，证实了CXCR4影响MSCs迁移的特异性。在足够浓度的SDF-1诱导下，未发现急性髓系白血病(AML)患者的BM-MSCs有内在因素缺陷影响其的迁移能力。提示AML患者BM-MSCs的迁移和归巢可能受骨髓微环境的改变影响。