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Impaired steel factor responsiveness differentially affects the detection
and long-term maintenance of fetal liver hematopoietic stem cells in vivo
CL Miller, VI Rebel, CD Helgason, PM Lansdorp and CJ Eaves
Terry Fox Laboratory, British Columbia Cancer Agency, Canada.
The results of previous studies have shown that the development of
hematopoiesis during fetal life can occur in the absence of Steel factor
(SF) signaling. On the other hand, impairment of this mechanism can
severely compromise the ability of cells from adult bone marrow to
regenerate hematopoiesis on their transplantation into myeloablated
recipients. This apparent paradox could result from changes during ontogeny
in the responsiveness of hematopoietic stem cells to regulators that may
substitute for SF as well as from differences in the availability of such
factors during embryogenesis and in the myeloablated adult. To investigate
these possibilities, we studied the effect of W41 and W42 mutations on the
numbers, phenotype, and posttransplant self-renewal behavior of primitive
hematopoietic cells present in the fetal liver (FL) of 14.5-day-old mouse
embryos. In W41/ W41 FL, day-12 spleen colony-forming units and long-term
culture- initiating cells appeared both quantitatively and qualitatively
similar to their counterparts in the FL of +/+ embryos. W41/W41 FL also
contained near normal numbers (approximately 50% of controls) of
transplantable lymphomyeloid stem cells with competitive reconstituting
ability in myeloablated adult +/+ recipients (as assessed for up to at
least 16 weeks posttransplant). Moreover, both the original phenotype of
these W41/W41 competitive repopulating units (CRUs) and their clonal
posttransplant output of mature progeny were normal. Similarly, when
myeloablated adult +/+ mice were cotransplanted with 5 x 10(4) +/+ FL cells
and a sevenfold to 70-fold excess of W41/W41 FL CRUs, the contribution of
the +/+ FL CRUs to the circulating white blood cell count present 5 weeks
later was markedly reduced as compared with that of mice that received only
+/+ FL cells. However, over the next 3 months, the proportion of mature
white blood cells that were derived from +/+ precursors increased
significantly (P < .002) in all groups (to > or = 30%), indicating
that the ability to sustain hematopoiesis beyond 5 weeks is more
SF-dependent than the ability to initially reconstitute both lymphoid and
myeloid compartments. Cells from individual FL of W42/+ matings also showed
an initial ability (at 7 to 8 weeks posttransplant) to competitively
repopulate both lymphoid and myeloid compartments of myeloablated +/+ adult
recipients. However, in contrast to recipients of normal or W41/W41 FL
cells, the repopulation obtained with the W42 mutant stem cells was
transient. Secondary transplants confirmed the inability of the W42 mutant
cells to regenerate or even maintain a population of transplantable stem
cells. Taken together with previous results from studies of CRUs in adult W
mice, these findings support the concept of changes in the way
hematopoietic stem cells at different stages of development respond to the
stimulatory conditions evoked in the myeloablated recipient. In addition,
they provide the first definitive evidence that SF is a limiting
physiological regulator of sustained hematopoietic stem cell self-renewal
in vivo.
Volume 89,
Issue 4,
pp. 1214-1223,
02/15/1997
Copyright © 1997 by The American Society of Hematology
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