Ohneda O, Fennie C, Zheng Z, Donahue C, La H, Villacorta R, Cairns B, Lasky L A
Departments of Molecular Oncology, Immunology, and Pathology, Genentech, Inc, South San Francisco, CA, USA.
Blood. 1998 Aug 1;92(3):908-19.
Hematopoietic stem cells are capable of extensive self-renewal and expansion, particularly during embryonic growth. Although the molecular mechanisms involved with stem cell maintenance remain mysterious, it is now clear that an intraembryonic location, the aorta-gonad-mesonephros (AGM) region, is a site of residence and, potentially, amplification of the definitive hematopoietic stem cells that eventually seed the fetal liver and adult bone marrow. Because several studies suggested that morphologically defined hematopoietic stem/progenitor cells in the AGM region appeared to be attached in clusters to the ventrally located endothelium of the dorsal aorta, we derived cell lines from this intraembryonic site using an anti-CD34 antibody to select endothelial cells. Analysis of two different AGM-derived CD34(+) cell lines revealed that one, DAS 104-8, efficiently induced fetal-liver hematopoietic stem cells to differentiate down erythroid, myeloid, and B-lymphoid pathways, but it did not mediate self-renewal of these pluripotent cells. In contrast, a second cell line, DAS 104-4, was relatively inefficient at the induction of hematopoietic differentiation. Instead, this line provoked the expansion of early hematopoietic progenitor cells of the lin-CD34(+)Sca-1(+)c-Kit+ phenotype and was proficient at maintaining fetal liver-derived hematopoietic stem cells able to competitively repopulate the bone marrow of lethally irradiated mice. These data bolster the hypothesis that the endothelium of the AGM region acts to mediate the support and differentiation of hematopoietic stem cells in vivo.
造血干细胞能够进行广泛的自我更新和扩增，尤其是在胚胎发育期间。尽管与干细胞维持相关的分子机制仍然神秘，但现在很清楚，胚胎内的一个位置，即主动脉-性腺-中肾（AGM）区域，是最终定植于胎儿肝脏和成人骨髓的定型造血干细胞的驻留位点，并且可能是其扩增位点。由于多项研究表明，AGM区域中形态学上定义的造血干/祖细胞似乎以簇状附着于背主动脉腹侧的内皮，我们使用抗CD34抗体从这个胚胎内位点衍生出细胞系，以选择内皮细胞。对两种不同的源自AGM的CD34(+)细胞系的分析表明，其中一个细胞系DAS 104-8能够有效地诱导胎儿肝脏造血干细胞沿红系、髓系和B淋巴细胞系途径分化，但它不能介导这些多能细胞的自我更新。相比之下，第二个细胞系DAS 104-4在诱导造血分化方面相对效率较低。相反，该细胞系能促使lin-CD34(+)Sca-1(+)c-Kit+表型的早期造血祖细胞扩增，并且能够有效地维持源自胎儿肝脏的造血干细胞，使其能够竞争性地重新填充经致死性照射小鼠的骨髓。这些数据支持了这样一种假说，即AGM区域的内皮在体内起到介导造血干细胞的支持和分化作用。
