Role of Members of the Wnt Gene Family in Human Hematopoiesis

Abstract

The hematopoietic system is derived from ventral mesoderm. A number of genes that are important in mesoderm development have been identified including members of the transforming growth factor-β (TGF-β) superfamily, the fibroblast growth factor (FGF) family, and the Wnt gene family. Because TGF-β plays a pleiotropic role in hematopoiesis, we wished to determine if other genes that are important in mesoderm development, specifically members of theWnt gene family, may play a role in hematopoiesis. Three members of the Wnt gene family (Wnt-5A, Wnt-2B, and Wnt-10B) were identified and cloned from human fetal bone stromal cells. These genes are expressed to varying levels in hematopoietic cell lines derived from T cells, B cells, myeloid cells, and erythroid cells; however, only Wnt-5A was expressed in CD34+Lin− primitive progenitor cells. The in vitro biological activity of these Wnt genes on CD34+Lin− hematopoietic progenitors was determined in a feeder cell coculture system and assayed by quantitating progenitor cell numbers, CD34+ cell numbers, and numbers of differentiated cell types. The number of hematopoietic progenitor cells was markedly affected by exposure to stromal cell layers expressing Wnt genes with 10- to 20-fold higher numbers of mixed colony-forming units (CFU-MIX), 1.5- to 2.6-fold higher numbers of CFU-granulocyte macrophage (CFU-GM), and greater than 10-fold higher numbers of burst-forming units-erythroid (BFU-E) in the Wnt-expressing cocultures compared with the controls. Colony formation by cells expanded on theWnt-expressing cocultures was similar for each of the three genes, indicating similar action on primitive progenitor cells; however, Wnt-10B showed differential activity on erythroid progenitors (BFU-E) compared with Wnt-5A and Wnt-2B. Cocultures containing Wnt-10B alone or in combination with all three Wnt genes had threefold to fourfold lower BFU-E colony numbers than the Wnt-5A– or Wnt-2B–expressing cocultures. The frequency of CD34+ cells was higher inWnt-expressing cocultures and cellular morphology indicated that coculture in the presence of Wnt genes resulted in higher numbers of less differentiated hematopoietic cells and fewer mature cells than controls. These data indicate that the gene products of theWnt family function as hematopoietic growth factors, and that they may exhibit higher specificity for earlier progenitor cells. © 1998 by The American Society of Hematology.

WNT-conditioned media differentially affect the proliferation and differentiation of cord blood-derived CD133+ cells in vitro

“…The finding that WNT5a-CM reduced the proportion of early cells under these conditions is interesting, because stromal contact culture on WNT5a-overexpressing cells has previously been reported to have the opposite effect (Van Den Berg et al, 1998). This is consistent with at least some of the effects of WNT signaling being dependent on their presentation in a membrane-bound context.…”

Wnt10b promotes growth of hair follicles via a canonical Wnt signalling pathway

“…Van Den Berg et al 15 reported that Wnt10b could induce the proliferation of haematopoietic stem cells, and Lane et al 16 reported that overexpression of Wnt10b resulted in the hypermorphic development and transformation in he mammary glands of mice. These results indicate that Wnt10b plays a role in the proliferation of cells and tissues.…”

Regulation of dendritic cell differentiation and function by Notch and Wnt pathways

“…Wnt and their receptors are expressed in both hematopoietic progenitor cells (HPCs) and the surrounding bone marrow stroma (BMS) in both human and mouse, indicating that Wnt can be involved in HPC differentiation in a paracrine or autocrine fashion (33)(34)(35)(36). Treatment of hematopoietic stem cells (HSCs) with Wnt ligands stimulated a significant expansion of hematopoietic cells via activation of canonical pathway (34,(37)(38)(39).…”