Reikvam Håkon, Brenner Annette K, Hagen Karen Marie, Liseth Knut, Skrede Silje, Hatfield Kimberley Joanne, Bruserud Øystein
Section for Hematology, Department of Clinical Science, University of Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway; Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway.
Section for Hematology, Department of Clinical Science, University of Bergen, Norway.
Stem Cell Res. 2015 Nov;15(3):530-541. doi: 10.1016/j.scr.2015.09.008. Epub 2015 Sep 25.
Interactions between acute myeloid leukemia (AML) blasts and neighboring stromal cells are important for disease development and chemosensitivity. However, the molecular mechanisms involved in the cytokine-mediated crosstalk between mesenchymal stem cells (MSCs) and AML cells are largely unknown. Leukemic cells derived from 18 unselected AML patients were cultured with bone marrow MSCs derived from healthy donors; the populations then being separated by a semipermeable membrane. Coculture had only minor effects on MSC proliferation. The unique cytokine network in cocultures was determined by high constitutive MSC release of certain cytokines (especially IL-6 and vascular endothelial growth factor) and constitutive release of a wide range of soluble mediators by primary AML cells. However, the AML cell release varied considerably between patients, and these differences between patients were also reflected in the coculture levels even though supra-additive effects were seen for many mediators. These effects on the local cytokine network were dependent on a functional crosstalk between the two cell subsets. The crosstalk altered the global gene expression profile of the MSCs, especially expression of genes encoding proteins involved in downstream signaling from Toll like receptors, NFκB signaling and CCL/CXCL chemokine release. Thus, primary AML cells alter the functional phenotype of normal MSCs.
急性髓系白血病（AML）原始细胞与邻近基质细胞之间的相互作用对疾病发展和化疗敏感性至关重要。然而，间充质干细胞（MSC）与AML细胞之间细胞因子介导的串扰所涉及的分子机制在很大程度上尚不清楚。将来自18例未经选择的AML患者的白血病细胞与来自健康供体的骨髓MSC共同培养；然后通过半透膜将细胞群体分开。共培养对MSC增殖只有轻微影响。共培养中独特的细胞因子网络由某些细胞因子（特别是IL-6和血管内皮生长因子）的高组成性MSC释放以及原代AML细胞对多种可溶性介质的组成性释放所决定。然而，AML细胞的释放因患者而异，尽管许多介质出现超加性效应，但患者之间的这些差异也反映在共培养水平上。这些对局部细胞因子网络的影响取决于两个细胞亚群之间的功能性串扰。这种串扰改变了MSC的整体基因表达谱，特别是编码参与Toll样受体下游信号传导、NFκB信号传导和CCL/CXCL趋化因子释放的蛋白质的基因的表达。因此，原代AML细胞改变了正常MSC的功能表型。
