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Prepublished online as a Blood First Edition Paper on April 3, 2003; DOI 10.1182/blood-2002-06-1694.
Submitted June 10, 2002
Accepted March 25, 2003
Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells
Ewa Sitnicka*, Natalija Buza-Vidas, Staffan Larsson, Jens M Nygren, Karina Liuba, and Sten Eirik W Jacobsen
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden
* Corresponding author; email: ewa.sitnicka{at}stemcell.lu.se.
The cytokine tyrosine kinase receptors c-kit and flt3 have been demonstrated to be expressed and function in early mouse and human hematopoiesis. Through its ability to promote ex vivo expansion and oncoretroviral transduction of primitive human hematopoietic progenitors, the flt3 ligand (FL) has emerged as a key stimulator of candidate human hematopoietic stem cells (HSC). However, recent studies in the mouse suggest that although present on short-term repopulating cells, flt3 is not expressed on bone marrow long-term reconstituting hematopoietic stem cells, the ultimate target for development of cell replacement and gene therapy. Herein we demonstrate that although only a fraction of human adult bone marrow and cord blood CD34+ long-term culture-initiating cells (LTC-IC) express flt3, the majority of cord bloodlympho-myeloid HSC capable of in vivo reconstituting NOD/SCID mice are flt3+. Importantly, the striking difference in flt3 and c-kit expression on mouse and candidate human HSC, translated into a corresponding difference in flt3 and c-kit function, since FL was more efficient than SCF at supporting survival of candidate human HSC. In contrast, SCF is far superior to FL as a viability factor for mouse HSC. Thus, the present data provide compelling evidence for a contrasting expression and response pattern of flt3 and c-kit on mouse and human HSC.
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