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

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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.