Nature Medicine9, 1423 - 1427 (2003)
Published online: 26 October 2003; | doi:10.1038/nm953
Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein
Sophie Amsellem1, Françoise Pflumio1, Dominique Bardinet1, Brigitte Izac1, Pierre Charneau2, Paul-Henri Romeo1, Anne Dubart-Kupperschmitt1
& Serge Fichelson1, 3
1
Institut Cochin, Département d'Hématologie, INSERM U567, CNRS UMR 8104, Université Paris 5, Maternité Port-Royal, 123, Bd de Port-Royal, 75014 Paris, France.
2
Unité d'Oncologie Virale, Institut Pasteur, 25−28 rue du Dr Roux, 75015 Paris, France.
3
AP-HP, Hôpital Cochin, 27 rue du Fg St Jacques, 75014 Paris, France.
Expansion of human hematopoietic stem cells (HSCs) is a major challenge in cellular therapy, and currently relies on the use of recombinant cytokines or on gene transfer of transcription factors. Of these, the HOXB4 homeoprotein protein is of particular interests as it promotes the expansion of mouse HSCs without inducing the development of leukemia. To eliminate any deleterious effects that might be associated with stable HOXB4 gene transfer into human cells, we took advantage of the ability of HOX proteins to passively translocate through cell membranes. Here we show that when cultured on stromal cells genetically engineered to secrete HOXB4, human long-term culture-initiating cells (LTC-ICs) and nonobese diabetic−severe combined immunodeficiency (NOD-SCID) mouse repopulating cells (SRCs) were expanded by more than 20- and 2.5-fold, respectively, over their input numbers. This expansion was associated with enhanced stem cell repopulating capacity in vivo and maintenance of pluripotentiality. This method provides a basis for developing cell therapy strategies using expanded HSCs that are not genetically modified.
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