WNT proteins: environmental factors regulating HSC fate in the niche.

The Wnt signaling pathway has been implicated in regulation of hematopoiesis through a plethora of studies from many different laboratories. However, different inducible gain- and loss-of-function approaches retrieved controversial and sometimes contradictory results. Different levels of activation of the pathway, dosages of Wnt signaling required, and the interference by other signals in the context of Wnt activation collectively explain these controversies. Gain-of-function or in vitro exposure to WNT proteins and more specifically WNT3a was shown to enhance hematopoietic stem cell (HSC) activity, but its exact role was still not completely understood. In a recent study we analyzed the hematopoietic system of mice deficient for this specific Wnt gene. Wnt3a deficiency results in early embryonic lethality around embryonic day 12.5 (E12.5), precluding analysis in adult mice, but allowing hematopoiesis to be studied in fetal liver (FL) and in the just colonized thymic rudiment. Notably, we showed that long-term HSCs and multipotent progenitors are reduced in FL and have severely reduced long-term reconstitution capacity as observed in serial transplantation assays. Of interest, deficiency in Wnt3a leads to complete abolition of canonical Wnt signaling in FL hematopoietic stem and progenitor cells. This HSC deficiency is not explained by altered cell cycle or survival and is irreversible, since it cannot be restored by transplantation into Wnt3a-competent mice. In addition, Wnt3a deficiency differentially affects myeloid and B-lymphoid lineages, with myeloid cells being affected at the progenitor level, while B lymphopoiesis is apparently unaffected. Immature thymocytes, however, were reduced in cell numbers due to lack of Wnt3a production by the thymic microenvironment. Our results show that while in the thymus Wnt3a provides cytokine-like, proliferative stimuli to developing thymocyte Wnt3a regulates cell fate decisions of FL HSC in a nonredundant way.