The competitive nature of HOXB4-transduced HSC is limited by PBX1: the generation of ultra-competitive stem cells retaining full differentiation potential.
We previously showed that HOXB4 is a potent stimulator of hematopoietic stem cell (HSC) proliferation in vivo and ex vivo. As a result, HOXB4 overexpressing HSCs are 20- to 50-times more competitive than untransduced cells when transplanted into mice. By knocking down the expression of PBX1 (PBX1(K.D.)) in HOXB4 overexpressing cells, we now present the possibility of generating HSCs that are >20-times more competitive than those that overexpress HOXB4. The differentiation activity of these cells appears intact, since they competitively contributed to the reconstitution of normal myeloid and lymphoid compartments in vivo. We also show that the in vivo expansion of HOXB4-PBX1(K.D.)-expressing HSCs regenerated normal stem cell pools and did not lead to HSC levels above those detected in unmanipulated mice. The vigorous competitive nature of these cells in vivo compared to HOXB4-transduced HSCs suggests the existence of a distinct, non-cell autonomous mechanism that limits the expansion of HOXB4-transduced hemopoietic stem cells in mice.
Krosl
Jana
J
Laboratory of Molecular Genetics, Hemopoietic Stem Cells, Clinical Research Institute of Montréal, Québec, Canada H2W 1R7.
Beslu
Nathalie
N
Mayotte
Nadine
N
Humphries
R Keith
RK
Sauvageau
Guy
G
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002454:Cell Differentiation; D002455:Cell Division; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D014157:Transcription Factors