An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.
An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.
复制标题
骨髓微环境异常导致范可尼贫血的造血功能障碍
DOI：
10.3324/haematol.2016.158717
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发表时间：
2017-06
期刊：
影响因子：
10.1
通讯作者：
Yang FC
中科院分区：
文献类型：
--
作者：
Zhou Y;He Y;Xing W;Zhang P;Shi H;Chen S;Shi J;Bai J;Rhodes SD;Zhang F;Yuan J;Yang X;Zhu X;Li Y;Hanenberg H;Xu M;Robertson KA;Yuan W;Nalepa G;Cheng T;Clapp DW;Yang FC
范可尼贫血是一种复杂的异质性遗传性疾病，具有高发生率的骨髓衰竭，克隆演变为急性髓性白血病和间充质源性先天性异常。越来越多的证据表明范可尼贫血和其他遗传性疾病指向骨骼和造血发育的相互依赖性，但骨髓微环境在范可尼贫血骨髓衰竭发病机制中的影响仍不清楚。在这里，我们证明了Fancc和Fancg基因双敲除的小鼠骨形成减少，至少部分是由于间充质干细胞/祖细胞的成骨细胞分化受损。来自双基因敲除小鼠的间充质干/祖细胞表现出受损的造血支持活性。范可尼贫血患者的间充质干/祖细胞表现出类似的细胞缺陷，包括衰老增加、增殖减少、成骨细胞分化受损和造血干/祖细胞支持活性缺陷。总的来说，这些研究提供了独特的见解间充质干细胞/祖细胞在支持骨髓微环境，这是潜在的造血干细胞移植的广泛相关的生理意义。
Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.