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.
The cytokine tyrosine kinase receptors c-kit and flt3 are 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 (HSCs). However, recent studies in the mouse suggest that though it is present on short-term repopulating cells, flt3 is not expressed on bone marrow long-term reconstituting HSCs, the ultimate target for the development of cell replacement and gene therapy. Herein we demonstrate that though only a fraction of human adult bone marrow and cord blood CD34+long-term culture-initiating cells (LTC-ICs) express flt3, most cord blood lymphomyeloid HSCs capable of in vivo reconstituting nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice are flt3+. The striking difference in flt3 and c-kit expression on mouse and candidate human HSCs translated into a corresponding difference in flt3 and c-kit function because FL was more efficient than SCF at supporting the survival of candidate human HSCs. In contrast, SCF is far superior to FL as a viability factor for mouse HSCs. Thus, the present data provide compelling evidence for a contrasting expression and response pattern of flt3 and c-kit on mouse and human HSCs.
Sitnicka
Ewa
E
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, BMC, B10, Klinikgatan 26, 221-84 Lund, Sweden. ewa.sitnicka@stemcell.lu.se
Buza-Vidas
Natalija
N
Larsson
Staffan
S
Nygren
Jens M
JM
Liuba
Karina
K
Jacobsen
Sten Erik W
SE
D000818:Animals; D018952:Antigens, CD34; D001853:Bone Marrow / Q000378:metabolism; D002470:Cell Survival; D005312:Fetal Blood / Q000166:cytology; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D038041:Lymphopoiesis; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D038042:Myelopoiesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology*; D019089:Stem Cell Factor; D014183:Transplantation, Heterologous; D051941:fms-Like Tyrosine Kinase 3
D018952:Antigens, CD34; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019089:Stem Cell Factor; C084881:flt3 ligand protein; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3