Enhanced in vivo regenerative potential of HOXB4-transduced hematopoietic stem cells with regulation of their pool size.
After bone marrow transplantation (BMT), there is a rapid regeneration to normal pretransplantation levels in the number of hematopoietic progenitors and mature end cells, whereas hematopoietic stem cell (HSC) numbers recover to only 5% to 10% of normal levels. This suggests that HSC are significantly restricted in their self-renewal behavior and hence in their ability to repopulate the host stem cell compartment. Previously, we have reported that HSC engineered to overexpress the homeobox transcription factor HOXB4 have a large repopulation advantage over untransduced cells as assessed at 4 months in a murine transplantation model (Sauvageau et al, Genes Dev 9:1753, 1995). This phenomenon has now been examined in detail for periods extending to 12 months in cohorts of mice transplanted with various numbers of HOXB4-transduced HSC. In all mice analyzed, HOXB4-transduced HSC were capable of fully reconstituting the HSC compartment, resulting, on average, in some 14-fold greater numbers of HSC than observed when transplanting control, non-HOXB4-transduced bone marrow cells. These data indicate that HOXB4 is a limiting factor in the regeneration of HSC to normal levels after BMT. Furthermore, we show that HOXB4-transduced HSC did not expand above levels normally observed in unmanipulated mice, indicating that its overexpression does not override the regulatory mechanisms that maintain the HSC pool size within normal limits.
Thorsteinsdottir
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Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Sauvageau
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Humphries
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RK
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002452:Cell Count; D002455:Cell Division; D002478:Cells, Cultured / Q000637:transplantation; D003114:Colony-Forming Units Assay; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors