Identification of a Stroma‐Mediated Wnt/β‐Catenin Signal Promoting Self‐Renewal of Hematopoietic Stem Cells in the Stem Cell Niche

With contrasting observations on the effects of β‐catenin on hematopoietic stem cells (HSCs), the precise role of Wnt/β‐catenin signals on HSC regulation remains unclear. Here, we show a distinct mode of Wnt/β‐catenin signal that can regulate HSCs in a stroma‐dependent manner. Stabilization of β‐catenin in the bone marrow stromal cells promoted maintenance and self‐renewal of HSCs in a contact‐dependent manner, whereas direct stabilization in hematopoietic cells caused loss of HSCs. Interestingly, canonical Wnt receptors and β‐catenin accumulation were predominantly enriched in the stromal rather than the hematopoietic compartment of bone marrows. Moreover, the active form of β‐catenin accumulated selectively in the trabecular endosteum in “Wnt 3a‐stimulated” or “irradiation‐stressed,” but not in “steady‐state” marrows. Notably, notch ligands were induced in Wnt/β‐catenin activated bone marrow stroma and downstream notch signal activation was seen in the HSCs in contact with the activated stroma. Taken together, Wnt/β‐catenin activated stroma and their cross‐talk with HSCs may function as a physiologically regulated microenvironmental cue for HSC self‐renewal in the stem cell niche. STEM CELLS 2009;27:1318–1329