Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg-/- mice in vivo
Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg-/- mice in vivo
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DOI：
10.1182/blood-2008-07-168138
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发表时间：
2009-03-05
期刊：
影响因子：
20.3
通讯作者：
Yang, Feng-Chun
中科院分区：
文献类型：
--
作者：
Li, Yan;Chen, Shi;Yang, Feng-Chun
范可尼贫血（FA）是一种异质性遗传性疾病，其特征是骨髓衰竭和复杂的先天性异常。尽管FA基因突变导致造血干/祖细胞（HSPC）的特征表型，但对其他干/祖细胞隔室中无功能FA通路的后果知之甚少。鉴于HSPCs和间充质微环境之间的强烈功能相互作用，我们研究了FA途径对小鼠间充质干/祖细胞（MSPCs）的细胞功能及其与HSPCs的相互作用。在这里，我们表明，FANCG（Fancg）的小鼠同源物的损失导致MSPC增殖的缺陷，并在他们的能力，以支持在体外或体内的小鼠同源HSPC的粘附和植入。将野生型（WT）而非Fancg（-/-）MSPC移植到Fancg（-/-）受体小鼠的胫骨中增强了HSPC移植动力学、BM细胞构成以及注射到致死性辐照的Fancg（-/-）受体中的WT HSPC的每个胫骨的祖细胞数量。总的来说，这些数据表明，BM微环境中需要FA蛋白来维持正常的造血作用，并提供了WT MSPC过继转移增强造血干细胞植入的遗传和定量证据。（血。2009; 113：2342-2351）
Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow failure and complex congenital anomalies. Although mutations in FA genes result in a characteristic phenotype in the hematopoietic stem/progenitor cells (HSPCs), little is known about the consequences of a nonfunctional FA pathway in other stem/progenitor cell compartments. Given the intense functional interactions between HSPCs and the mesenchymal microenvironment, we investigated the FA pathway on the cellular functions of murine mesenchymal stem/progenitor cells (MSPCs) and their interactions with HSPCs in vitro and in vivo. Here, we show that loss of the murine homologue of FANCG (Fancg) results in a defect in MSPC proliferation and in their ability to support the adhesion and engraftment of murine syngeneic HSPCs in vitro or in vivo. Transplantation of wild-type (WT) but not Fancg(-/-) MSPCs into the tibiae of Fancg(-/-) recipient mice enhances the HSPC engraftment kinetics, the BM cellularity, and the number of progenitors per tibia of WT HSPCs injected into lethally irradiated Fancg(-/-) recipients. Collectively, these data show that FA proteins are required in the BM microenvironment to maintain normal hematopoiesis and provide genetic and quantitative evidence that adoptive transfer of WT MSPCs enhances hematopoietic stem cell engraftment. (Blood. 2009; 113: 2342-2351)