LAUSR

Stem cell niches are specialized microenvironments that regulate stem cell-specific properties, including multipotentiality, self-renewal, and quiescence. Wnt signaling in stem cell niches plays a critical role in regulating stem cells from multiple tissues, including embryonic, epidermal, intestinal, and hematopoietic stem cells (HSCs).1 In the canonical Wnt pathway, Wnt ligand binds to its receptor Frizzled (Fz) at the cell surface and inhibits glycogen synthase kinase3β (GSK-3β)-mediated phosphorylation and degradation of β-catenin. Stabilized β-catenin then translocates to the nucleus where it binds to T cell factor/lymphoid enhancer factor transcription factors and induces target gene expression.1 In the absence of Wnt ligand, GSK3β phosphorylates β-catenin and targets it for ubiquitination and degradation.1 In addition to canonical Wnt signaling pathway, specific Wnt ligands can also activate the noncanonical Wnt signaling pathways independent of β-catenin. Noncanonical Wnt signaling regulates cellular polarization, controls nuclear localization of NFAT transcriptional factor, and suppresses canonical Wnt signaling.1 Thus, the functional interplay between canonical and noncanonical Wnt signaling in stem cell niches dictates cell fates during development. The purpose of this commentary is to summarize what we know about Wnt signaling in hematopoiesis and clarify some conflictual findings in the field. HSCs differ during ontogeny in some important parameters, including anatomic site of residence and cell cycle status.2 Fetal HSCs reside in the fetal liver and are highly proliferative, contributing to HSC expansion.2 Adult HSCs mainly reside in the bone marrow (BM) and are more quiescent, promoting HSC self-renewal and maintenance.2 In this issue of Journal of Leukocyte Biology, Heinonen and her laboratory team investigated the activities of canonical and noncanonical Wnt signaling pathways in murine fetal as well as adult hematopoietic stem and progenitors (HSPCs).3 They found that the expression of canonicalWnt/β-catenin signaling genes is increased in fetal HSPCs compared with adult HSPCs. Notably, they observed higher levels of intracellular β-catenin in fetalHSPCs compared to adultHSPCsby flow cytometry analysis,3 confirming earlier findings using canonical Wnt reporter mice that fetal HSPCs have higher Wnt/β-catenin activity thanadultHSPCs.4 Further, the authors showed that changes in canonicalWnt activity in fetal and adult HSPCs are not associated with their cell cycle status. Interestingly, the expression of several noncanonical Wnt signaling genes is down-regulated in fetal HSPCs compared with