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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2605-2612
Enhanced In Vivo Regenerative Potential of HOXB4-Transduced
Hematopoietic Stem Cells With Regulation of Their Pool Size
Unnur Thorsteinsdottir,
Guy Sauvageau, and
R. Keith Humphries
From the Terry Fox Laboratory, British Columbia Cancer Agency,
Vancouver, British Columbia, Canada; and the Department of Medicine,
University of British Columbia, Vancouver, British Columbia, Canada.
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.
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