Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment.
Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment.
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DOI：
10.1038/nature08099
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发表时间：
2009-07-09
期刊：
影响因子：
64.8
通讯作者：
Daley, George Q.
中科院分区：
文献类型：
--
作者：
Naveiras, Olaia;Nardi, Valentina;Wenzel, Pamela L.;Hauschka, Peter V.;Fahey, Frederic;Daley, George Q.
在哺乳动物骨髓中，成骨细胞和内皮细胞构成支持造血干细胞(HSC)的功能生态位。成人骨髓中也含有脂肪细胞，其数量与骨髓的造血活性成反比。放疗或化疗后，造血性红骨髓脂肪渗出，这是骨髓再生障碍性贫血患者活检的一个诊断特征。为了探索脂肪细胞是影响造血还是只是填充骨髓间隙，我们比较了不同脂肪含量的小鼠骨骼不同区域的造血活性。通过流式细胞术、集落形成活性和竞争性再繁殖试验，相对于不含脂肪细胞的胸椎，小鼠尾部富含脂肪细胞的椎体中的HSCs和短期祖细胞的频率减少。在基因上不能形成脂肪细胞的脂肪萎缩性A-ZIP/F1“无脂”小鼠，以及用抑制脂肪生成的PPARγ抑制剂双酚-A-二缩水甘油醚(BAGE)治疗的小鼠中，相对于野生型或未治疗的小鼠，照射后的骨髓移植加速。这些数据表明，脂肪细胞是骨髓微环境的主要负调控细胞，提示在临床骨髓移植中，拮抗骨髓脂肪生成可能会促进造血恢复。
Osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC) in mammalian bone marrow (BM) . Adult BM also contains adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. Fatty infiltration of hematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. To explore whether adipocytes influence hematopoiesis or simply fill marrow space, we compared the hematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. By flow cytometry, colony forming activity, and competitive repopulation assay, HSCs and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes, and in mice treated with the PPARγ inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE), which inhibits adipogenesis, post-irradiation marrow engraftment is accelerated relative to wild type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment, and suggest that antagonizingmarrow adipogenesis may enhance hematopoietic recovery in clinical bone marrow transplantation.
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