Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene.
Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene.
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DOI：
10.1084/jem.186.4.529
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发表时间：
1997-08-18
期刊：
影响因子：
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通讯作者：
Van Zant G
中科院分区：
文献类型：
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作者：
de Haan G;Van Zant G
我们评估了小鼠原始造血干细胞增殖和数量的外在（生长因子诱导的）和内在（遗传决定的）效应子之间的体内相互作用。因此，干细胞频率和细胞周期动力学进行了评估，在8个品系的近交系小鼠使用鹅卵石面积形成细胞（CAFC）测定。在小鼠寿命和股骨中自主循环祖细胞（CAFC第7天）的数量之间观察到强烈的负相关。原始干细胞（CAFC第35天）的群体大小在菌株之间变化很大（高达7倍），不像总CAFC第7天的数量（循环和静止），这是相似的。给这些菌株施用早期作用细胞因子flt-3配体导致仅在具有高内源性干细胞数量（DBA和AKR）的菌株中激活静止原始干细胞，但与菌株特异性祖细胞循环无关。为了绘制影响干细胞频率的基因座，我们定量了BXD重组近交系小鼠（C57 BL/6和DBA/2的后代）中的干细胞。由此产生的菌株分布模式显示出与定位于染色体18（19 cM）的标记高度一致。与该基因组间隔的连锁与3.3的比值分数的可能性相关，超过了显著性所需的水平。有趣的是，含有EGR-1基因的这一片段显示出与人类染色体5 q的同线性，该区域与各种血液恶性肿瘤密切相关。我们的研究结果表明，在C57 BL/6或DBA/2（可能还有AKR）小鼠中，定位到该区域的基因发生了突变。这些在表面上健康的小鼠中进行的研究可能有助于鉴定与人类5 q综合征有关的基因。
We evaluated in vivo interactions between extrinsic (growth factor induced) and intrinsic (genetically determined) effectors of mouse primitive hemopoietic stem cell proliferation and numbers. Accordingly, stem cell frequency and cell cycle kinetics were assessed in eight strains of inbred mice using the cobblestone area–forming cell (CAFC) assay. A strong inverse correlation was observed between mouse lifespan and the number of autonomously cycling progenitors (CAFC day 7) in the femur. The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar. Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling. To map loci affecting stem cell frequency, we quantified stem cells in BXD recombinant inbred mice (offspring of C57BL/6 and DBA/2). The resulting strain distribution pattern showed high concordance with a marker that mapped to chromosome 18 (19 cM). Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance. Interestingly, this segment, containing the EGR-1 gene, shows synteny with human chromosome 5q, a region strongly associated with various hematological malignancies. Our findings indicate that a gene mapping to this region is mutated in either C57BL/6 or DBA/2 (and possibly AKR) mice. These studies in apparently healthy mice may facilitate the identification of a gene implicated in human 5q-syndromes.