A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells.
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.
Austin
T W
TW
Department of Molecular Oncology, Genentech, Inc, South San Francisco, CA 94080, USA.
Solar
G P
GP
Ziegler
F C
FC
Liem
L
L
Matthews
W
W
D000818:Animals; D002455:Cell Division; D019070:Cell Lineage; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D005786:Gene Expression Regulation; D005865:Gestational Age; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000166:cytology*; D008099:Liver / Q000166:cytology / Q000196:embryology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D005810:Multigene Family; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011519:Proto-Oncogenes; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein; D015017:Yolk Sac / Q000166:cytology; D029961:Zebrafish Proteins
D017077:Culture Media, Conditioned; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C491119:WNT10B protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; C102068:Wnt10b protein, mouse; D029961:Zebrafish Proteins; C058784:fz protein, Drosophila