Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity.
Flt3 has emerged as a potential regulator of hematopoietic stem cells (HSC). Sixty percent of cells in the mouse marrow Lin(-)Sca1(+)c-kit(+) HSC pool expressed flt3. Although single cell cloning showed comparable high proliferative, myeloid, B, and T cell potentials of Lin(-)Sca1(+)c-kit(+)flt3(+) and Lin(-)Sca1(+)c-kit(+)flt3(-) cells, only Lin(-)Sca1(+)c-kit(+)flt3(-) cells supported sustained multilineage reconstitution. In striking contrast, Lin(-)Sca1(+)c-kit(+)flt3(+) cells rapidly and efficiently reconstituted B and T lymphopoiesis, whereas myeloid reconstitution was exclusively short term. Unlike c-kit, activation of flt3 failed to support survival of HSC, whereas only flt3 mediated survival of Lin(-)Sca1(+)c-kit(+)flt3(+) reconstituting cells. Phenotypic and functional analysis support that Lin(-)Sca1(+)c-kit(+)flt3(+) cells are progenitors for the common lymphoid progenitor. Thus, upregulation of flt3 expression on Lin(-)Sca1(+)c-kit(+) HSC cells is accompanied by loss of self-renewal capacity but sustained lymphoid-restricted reconstitution potential.
Adolfsson
J
J
Department of Stem Cell Biology, Institute of Laboratory Medicine, University Hospital of Lund, S-221 85 Lund, Sweden.
Borge
O J
OJ
Bryder
D
D
Theilgaard-Mönch
K
K
Astrand-Grundström
I
I
Sitnicka
E
E
Sasaki
Y
Y
Jacobsen
S E
SE
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D002478:Cells, Cultured; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D007700:Kinetics; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis*; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D019089:Stem Cell Factor / Q000494:pharmacology; D015854:Up-Regulation; D051941:fms-Like Tyrosine Kinase 3
D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019089:Stem Cell Factor; C084881:flt3 ligand protein; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3