Regulation of Hematopoietic Differentiation from Pluripotent Stem Cells by HOXB4 and Niche Factors

胚胎发育过程中造血干细胞（hsc）的产生在空间和时间上受到内在因素和外源性微环境“生态位”的严格控制。造血干细胞似乎是由胚胎血管中的造血内皮细胞新生产生的，它们在胚胎肝脏和成人骨髓中植入。当同源结构域转录因子HOXB4异位表达时，多能胚胎干细胞（ES-）的分化可以概括体外造血的许多方面，甚至可以在移植到受体小鼠体内后产生能够长期多系再生的细胞。因此，es细胞分化系统对于详细了解血液形成过程具有重要价值。此外，它在造血细胞和基因治疗方面也有广阔的应用前景。由于技术的到来，使我们能够重新编程体细胞回到es细胞样状态，从患者特异性的所谓诱导多能干细胞（iPS）细胞生成造血干细胞在未来的治疗应用中显示出巨大的希望。在这项中德联合应用中，我们将研究表达HOXB4的es细胞分化的规格和造血功能，以及新型利基衍生细胞系支持小鼠和人类多能干细胞体外生成完全成熟的造血干细胞的能力。

Generation of hematopoietic stem cells (HSCs) during embryonic development is spatially and temporally tightly controlled by intrinsic factors and the extrinsic microenvironment, the “niche”. HSCs appear to arise de novo from hemogenic endothelial cells residing in embryonic vessels from where they seed the fetal liver and the adult bone marrow. Differentiation of pluripotent embryonic stem (ES-) cells can recapitulate many aspects of hematopoiesis, in vitro, and can even generate cells capable of long-term multilineage repopulation after transplantation into recipient mice, when the homeodomain transcription factor HOXB4 is ectopically expressed. Thus, the ES-cell differentiation system is of great value for a detailed understanding of the process of blood formation. Furthermore, it is also promising for future application in hematopoietic cell- and gene therapy. Since the arrival of techniques which allow us to reprogram somatic cells back to an ES-cell like state, the generation of HSCs from patient-specific so-called induced pluripotent stem (iPS) cells shows great promise for future therapeutic applications. In this Chinese-German joint application, we will investigate the specification and hematopoietic commitment of differentiating ES-cells expressing HOXB4 and the capability of novel niche-derived cell lines to support the in vitro generation of fully mature HSCs from mouse and human pluripotent stem cells.