Furuta Chie, Ema Hideo, Takayanagi Shin-Ichiro, Ogaeri Takunori, Okamura Daiji, Matsui Yasuhisa, Nakauchi Hiromitsu
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Development. 2006 Jul;133(14):2771-9. doi: 10.1242/dev.02440.
Vasculogenesis and hematopoiesis are thought to arise in hemangioblasts, the common progenitors of cells in vessels and in blood. This scheme was challenged by kinetic analysis of vascular endothelial and hematopoietic progenitors in early gastrulating mouse embryos. The OP-9 co-culture system with a combination of cytokines permitted the detection of endothelial progenitors, as well as stroma-dependent hematopoietic progenitors. Endothelial progenitors were detected as early as embryonic day (E) 5.50, after which time their numbers increased. Stroma-dependent hematopoietic progenitors were detected at E6.75, the time point when hemangioblasts reportedly emerge. Colony-forming units in culture (CFU-c), most likely generated from stroma-dependent hematopoietic progenitors via contact with the microenvironment, were detected at E7.50, concomitant with the onset of primitive hematopoiesis in the yolk sac. The presence of nucleated erythrocytes and the expression of an embryonic-type globin in erythroid colonies derived from stroma-dependent hematopoietic progenitors and from CFU-c support the notion that these progenitors coordinately establish primitive hematopoiesis. Using Oct3/4 promoter-driven GFP transgenic mice, early endothelial progenitors, stroma-dependent hematopoietic progenitors, and CFU-c were all shown to express the Oct3/4 transcription factor. Among Oct3/4-positive cells, both endothelial and hematopoietic progenitors were present in the CD31-positive fraction, leaving a subset of endothelial progenitors in the CD31-negative fraction. These data imply that Oct3/4-positive mesoderm gives rise to CD31-negative angioblasts, CD31-positive angiboblasts and CD31-positive hemangioblasts. We propose a distinct developmental pathway in which the angioblast lineage directly diverges from mesoderm prior to and independent of hemangioblast development.
血管生成和造血作用被认为起源于成血管细胞，即成血管细胞是血管和血液中细胞的共同祖细胞。早期原肠胚形成的小鼠胚胎中血管内皮祖细胞和造血祖细胞的动力学分析对这一模式提出了挑战。OP-9共培养系统与细胞因子组合可检测到内皮祖细胞以及基质依赖性造血祖细胞。早在胚胎第（E）5.50天就检测到了内皮祖细胞，此后其数量增加。在E6.75天检测到基质依赖性造血祖细胞，据报道此时成血管细胞出现。培养中的集落形成单位（CFU-c）很可能是由基质依赖性造血祖细胞通过与微环境接触产生的，在E7.50天检测到，这与卵黄囊中原始造血作用的开始同时发生。来自基质依赖性造血祖细胞和CFU-c的红系集落中有核红细胞的存在以及胚胎型珠蛋白的表达支持了这些祖细胞协同建立原始造血作用的观点。使用Oct3/4启动子驱动的GFP转基因小鼠，早期内皮祖细胞、基质依赖性造血祖细胞和CFU-c均显示表达Oct3/4转录因子。在Oct3/4阳性细胞中，内皮祖细胞和造血祖细胞均存在于CD31阳性部分，而在CD31阴性部分留下一部分内皮祖细胞。这些数据表明，Oct3/4阳性中胚层产生CD31阴性成血管细胞、CD31阳性成血管细胞和CD31阳性成血管细胞。我们提出了一种独特的发育途径，即成血管细胞谱系在成血管细胞发育之前直接从中胚层分化出来，且独立于成血管细胞发育。
