Myelodysplastic Cells in Patients Reprogram Mesenchymal Stromal Cells to Establish a Transplantable Stem Cell Niche Disease Unit
Myelodysplastic Cells in Patients Reprogram Mesenchymal Stromal Cells to Establish a Transplantable Stem Cell Niche Disease Unit
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DOI：
10.1016/j.stem.2014.02.014
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发表时间：
2014-06-05
期刊：
影响因子：
23.9
通讯作者：
Nowak, Daniel
中科院分区：
文献类型：
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作者：
Medyouf, Hind;Mossner, Maximilian;Nowak, Daniel
骨髓增生异常综合征(MDS)是一组异质性的髓系肿瘤，具有造血干细胞和祖细胞(HSPC)缺陷，并可能存在HSPC生态位缺陷。在这里，我们发现患者来源的间充质基质细胞(MDS MSCs)表现出一种分化紊乱的程序，对于MDS启动的LI(-)CD34(+)CD38(-)干细胞在原位异种移植中的增殖是必不可少的。CDH2(N-钙粘附素)、IGFBP2、VEGFA和LIF等利基因子的过度产生与MDS MSCs促进MDS扩张的能力有关。这些因子代表了假定的治疗靶点，以破坏MDS中关键的造血-基质相互作用。最后，健康的MSCs在与造血MDS细胞接触时具有MDS MSC样的分子特征，这表明微环境的重建具有指导性意义。因此，这种患者来源的异种移植模型提供了功能和分子证据，表明MDS是一种同时涉及造血室和间质室的复杂疾病。由此导致的利基因子的表达失调也可能是其他血液系统恶性肿瘤的一个特征。
Myelodysplastic syndromes (MDSs) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem and progenitor cells (HSPCs) and possibly the HSPC niche. Here, we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating Li(-)CD34(+)CD38(-) stem cells in orthotopic xenografts. Overproduction of niche factors such as CDH2 (N-Cadherin), IGFBP2, VEGFA, and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets in order to disrupt critical hematopoietic- stromal interactions in MDS. Finally, healthy MSCs adopt MDS MSC-like molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of the microenvironment. Therefore, this patient-derived xenograft model provides functional and molecular evidence that MDS is a complex disease that involves both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies.