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 calls have been shown. The Wnt gene family is known to regulate the cell fate and cell-cell interactions df 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. (C) 1997 by The American Society of Hematology.