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

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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.