De novo Formation and Expansion of Multipotent Hematopoietic Stem and Progenitor Cells, directed by HOX Transcription Factors

造血干细胞（HSC）负责血细胞的终身生产。对于许多血液病，从健康供体获得的HSC制剂的移植是唯一的治愈性治疗选择。然而，这种治疗与严重的、潜在致命的排斥反应有关。因此，对于明确定义的遗传性疾病，患者自身HSC的体外基因修复是一种非常理想的替代方案。为此目的，单一处理和分子表征的HSC需要在体外扩增至治疗上合理的数量，或者由基因修复的患者特异性诱导多能干细胞（iPSC）产生。同源结构域（HOX）转录因子能够支持这两者，因为它们在胚胎造血发育期间起关键作用，并且还控制成体HSC的自我更新和分化。例如，H0XB 4的异位表达强制从分化的胚胎干细胞（ESC）产生HSC前体，并且还促进具有受限潜力的成体祖细胞的扩增。尽管如此，它不足以使ESC衍生的HSC完全成熟或扩增真正的多能HSC。因此，该授权申请的目的是发现新的HOX组合，其强制表达促进a）从分化的PSC形成完全成熟的HSC和B）介导成体HSC的选择性扩增。

Hematopoietic Stem Cells (HSCs) are responsible for the life-long production of blood cells. For many hematologic diseases, transplantation of HSC-preparations obtained from healthy donors is the only curative treatment option. However, this kind of therapy is associated with severe, potentially lethal rejection reactions. For well-defined inherited diseases, ex vivo gene repair of the patient´s own HSCs is, thus, a highly desirable alternative. For this purpose, single treated and molecularly characterized HSCs either need to be expanded, in vitro, up to therapeutically reasonable numbers or generated from gene-repaired, patient-specific induced pluripotent stem cells (iPSCs). Homeodomain (HOX) transcription-factors are capable of supporting both, as they play a key role during embryonic hematopoietic development and also control self-renewal and differentiation of adult HSCs. For example, ectopic expression of HOXB4 enforces the generation of HSC-precursors from differentiating embryonic stem cells (ESCs) and also promotes the expansion of adult progenitors with restricted potential. Nonetheless, it is not sufficient for a complete maturation of ESC-derived HSCs or for an expansion of truly multipotent HSCs. Thus, the aims of this grant application are to find novel HOX-combinations whose enforced expression promote a) the formation of fully mature HSCs from differentiating PSCs and b) mediate a selective expansion of adult HSCs.