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A role for the Wnt gene family in hematopoiesis: expansion of multilineage
progenitor cells
TW Austin, GP Solar, FC Ziegler, L Liem and W Matthews
Department of Molecular Oncology, Genentech, Inc, South San Francisco, CA
94080, USA.
The microenvironment is a key regulator of hematopoietic stem cells (HSCs)
and is a likely source of extracellular factors that control stem cell
fate. A better understanding of these microenvironmental factors may come
from investigations of developmental cell fate determination in which the
critical roles of cell-cell interactions of multipotential cells have been
shown. The Wnt gene family is known to regulate the cell fate and cell-cell
interactions of multipotential cells in a variety of tissues. Expression of
Wnts and of their putative receptors encoded by murine homologs of the
Drosophila frizzled gene in hematopoietic tissues was examined by reverse
transcriptase-polymerase chain reaction. Wnt-5a and Wnt-10b were expressed
in day-11 murine yolk sac, day-14 fetal liver, and fetal liver AA4+ cells.
The expression profiles of four murine frizzled homologs, Mfz3-7, were
nearly identical to that of Wnt-5a and Wnt-10b. Notably, Wnt-10b was
expressed in the fetal liver AA4+ Sca+ c-kit+ flASK) HSC population. A role
for Wnts in HSC fate determination was studied by treatment of HSC
populations in culture with soluble WNT proteins. The addition of
conditioned media from cells transfected with Wnt-1, Wnt-5a, or Wnt-10b
cDNAs to cultures of flASK cells stimulated a sevenfold, eightfold, and
11-fold expansion in cell number, respectively, relative to control media.
Removal of WNT-5a from this media by immunodepletion depleted the
stimulatory activity from the media, whereas addition of a partially
purified WNT-5a stimulated a fivefold expansion relative to control cells.
Transduction of flASK cells with a retrovirus bearing a Wnt-5a cDNA
enhanced proliferation. We conclude that WNTs stimulate the
survival/proliferation of hematopoietic progenitors, demonstrating that
WNTs comprise a novel class of hematopoietic cell regulators.
Volume 89,
Issue 10,
pp. 3624-3635,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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