A ROLE FOR THE WNT GENE FAMILY IN HEMATOPOIESIS - EXPANSION OF MULTILINEAGE PROGENITOR CELLS

The microenvironment is a key regulator of hematopoietic stem cells (H SCs) 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 multipotenti al calls have been shown. The Wnt gene family is known to regulate the cell fate and cell-cell interactions df multipotential cells in a var iety of tissues, Expression of Wnts and of their putative receptors en coded by murine homologs of the Drosophila frizzled gene in hematopoie tic tissues was examined by reverse transcriptase-polymerase chain rea ction, Wnt-5a and Wnt-10b were expressed in day-11 murine yolk sac, da y-14 fetal liver, and fetal liver AA4(+) cells. The expression profile s of four murine frizzled homologs, Mfz3-7, were nearly identical to t hat 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 medi a from cells transfected with Wnt-1, Wnt-5a, or Wnt-10b cDNAs to cultu res of flASK cells stimulated a sevenfold, eightfold, and 11 fold expa nsion 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, Transdu ction of flASK cells with a retrovirus bearing a Wnt-5a cDNA enhanced proliferation, We conclude that WNTs stimulate the survival/proliferat ion of hematopoietic progenitors, demonstrating that WNTs comprise a n ovel class of hematopoietic cell regulators. (C) 1997 by The American Society of Hematology.