Transient beta-catenin stabilization modifies lineage output from human thymic CD34+CD1a- progenitors

Increasing evidence includes Wnt proteins inside the group of master-signaling pathways that govern immune and nonimmune differentiation systems, fundamental for normal development and homeostasis. Although their precise functions in bone marrow and thymus are still controversial, numerous studies have shown that Wnt signaling is able to control the proliferation of hematopoietic stem cells and thymic progenitors and might also affect their cell-fate decisions and subsequent maturation. In the present work, we analyze the effect of transient stimulation of the canonical Wnt pathway in the differentiation potential of Lin(-)CD34(+) CD1a(-) human thymic progenitors, a multipotent and heterogeneous cell population that has the capacity to develop into T cells, NK cells, monocytes, cDC, and pDC. Our results demonstrate that giving a boost to canonical Wnt signaling, triggered by transient exposure to Wnt3a or LiCl, the differentiation capacity of thymic progenitors changes, enhancing NK cell production. On the contrary, Wnt3a- or LiCl-pretreated thymic progenitors generate a significantly lower number of myeloid lineage cells, monocytes, and cDC and exhibit a reduced capacity to differentiate into pDC lineage. As a possible mechanism for this effect, we show that Wnt3a- and LiCl-pretreated progenitors change their membrane levels of receptors for cytokines pivotal for their expansion and differentiation, such as Flt3L. Moreover, canonical Wnt pathway stimulation modifies the transcription factor profile of CD34(+)CD1(-) thymocytes, increasing Hes-1 and ID3 expression levels.