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Overexpression of HOXB4 enhances the hematopoietic potential of embryonic
stem cells differentiated in vitro
CD Helgason, G Sauvageau, HJ Lawrence, C Largman and RK Humphries
Department of Medicine, University of British Columbia, Vancouver, BC,
Canada.
Little is known about the molecular mechanisms controlling primitive
hematopoietic stem cells, especially during embryogenesis. Homeobox genes
encode a family of transcription factors that have gained increasing
attention as master regulators of developmental processes and recently have
been implicated in the differentiation and proliferation of hematopoietic
cells. Several Hox homeobox genes are now known to be differentially
expressed in various subpopulations of human hematopoietic cells and one
such gene, HOXB4, has recently been shown to positively determine the
proliferative potential of primitive murine bone marrow cells, including
cells with long-term repopulating ability. To determine if this gene might
influence hematopoiesis at the earliest stages of development, embryonic
stem (ES) cells were genetically modified by retroviral gene transfer to
overexpress HOXB4 and the effect on their in vitro differentiation was
examined. HOXB4 overexpression significantly increased the number of
progenitors of mixed erythroid/myeloid colonies and definitive, but not
primitive, erythroid colonies derived from embryoid bodies (EBs) at various
stages after induction of differentiation. There appeared to be no
significant effect on the generation of granulocytic or monocytic
progenitors, nor on the efficiency of EB formation or growth rate. Analysis
of mRNA from EBs derived from HOXB4-transduced ES cells on different days
of primary differentiation showed a significant increase in adult
beta-globin expression, with no detectable effect on GATA-1 or embryonic
globin (beta H-1). Thus, HOXB4 enhances the erythropoietic, and possibly
more primitive, hematopoietic differentiative potential of ES cells. These
results provide new evidence implicating Hox genes in the control of very
early stages in the development of the hematopoietic system and highlight
the utility of the ES model for gaining insights into the molecular genetic
regulation of differentiation and proliferation events.
Volume 87,
Issue 7,
pp. 2740-2749,
04/01/1996
Copyright © 1996 by The American Society of Hematology
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