Designer Cytokines for Human Haematopoietic Progenitor Cell Expansion: Impact for Tissue Regeneration

Haematopoietic stem cells after bone marrow transplantation can expand 100-fold and thereby completely reconstitute the haematopoietic system. Such an expansion has so far not been achieved in vitro using cytokines and growth factors. An interesting parallel exists betweenhaematopoietic stemcells andmouse embryonic stemcells. In both cell types, massive gp130 stimulation results in an inhibition of cellular differentiation. For both cell types, several intrinsic transcription factors are known which, when overexpressed, lead to massive self-renewal of the cells. It is currently unknown how in haematopoietic stem cells these intrinsic transcription factors, which include HOXB4 and Bmi-1, can be stimulated by extrinsic signals. Once such signals have been identified, they will be combined with the hyperstimulation of gp130 using designer cytokines. Additional strategies include a cellpermeable version of the HOXB4 protein and members of the WNTfamily of ligands. These strategies might eventually lead to an expansion of haematopoietic stem cells to a similar extent as that observed after bone marrow transplantation. Should haematopoietic stem cell expansion prove feasible and safe, there is great potential for the treatment of leukaemic disorders but also for the treatment of less severe diseases and non-malignant genetic disorders.