Inappropriate notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplastic syndromes

被引:45
|
作者
Varga, Gergely [2 ]
Kiss, Judit [1 ]
Varkonyi, Judit [2 ]
Vas, Virag [1 ]
Farkas, Peter
Paloczi, Katalin [2 ,3 ]
Uher, Ferenc [1 ]
机构
[1] Natl Med Ctr, Stem Cell Biol, H-1113 Budapest, Hungary
[2] Semmelweis Univ, Dept Internal Med 3, H-1085 Budapest, Hungary
[3] Natl Med Ctr, Dept Immunol, H-1113 Budapest, Hungary
关键词
cobblestone area-forming cells; Jagged-1; myelodysplastic syndromes; Notch signaling; stem cell plasticity;
D O I
10.1007/BF02940310
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Myelodysplastic syndromes (MDSs) are a heterogeneous group of hematological disorders characterized by ineffective hematopoiesis, enhanced bone marrow apoptosis and frequent progression to acute myeloid leukemia. Several recent studies suggested that, besides the abnormal development of stem cells, microenvironmental alterations are also present in the MDS bone marrow. In this study, we have examined the relative frequencies of stem and progenitor cell subsets of MDS and normal hematopoietic cells growing on stromal cell layers established from MDS patients and from normal donors. When hematopoietic cells from MDS patients were co-cultured with normal stromal cells, the frequency of either early or late cobblestone area-forming cells (CAFC) was significantly lower compared to the corresponding normal control values in 4 out of 8 patients. In the opposite situation, when normal hematopoietic cells were incubated on MDS stromal cells, the CAFC frequencies were decreased in 5 out of 6 patients, compared to normal stromal layer-containing control cultures. Moreover, a soluble Notch ligand (Jagged-1 protein) was an inhibitor of day-3542 CAFC when normal hematopoietic cells were cultured with normal or MDS stromal cells, but was unable to inhibit MDS stem and early progenitor cell growth (day-35-42 CAFC) on pre-established stromal layers. These findings suggest that in early hematopoietic cells isolated from MDS patients the Notch signal transduction pathway is disrupted. Furthermore, there was a marked reduction in the plasticity of mesenchymal stem cells of MDS patients compared with those of normal marrow donors, in neurogenic and adipogenic differentiation ability and hematopoiesis supporting capacity in vitro. These results are consistent with the hypothesis that when alterations are present in the myelodysplastic stroma environment along with intrinsic changes in a hematopoietic stem/ progenitor cell clone, both factors might equally contribute to the abnormal hematopoiesis in MDS.
引用
收藏
页码:311 / 319
页数:9
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