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

With contrasting observations on the effects of beta-catenin on hematopoietic stem cells (HSCs), the precise role of Wnt/beta-catenin signals on HSC regulation remains unclear. Here, we show a distinct mode of Wnt/beta-catenin signal that can regulate HSCs in a stroma-dependent manner. Stabilization of beta-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 beta-catenin accumulation were predominantly enriched in the stromal rather than the hematopoietic compartment of bone marrows. Moreover, the active form of beta-catenin accumulated selectively in the trabecular endosteum in Wnt 3a-stimulated or irradiationstressed, but not in steady- state marrows. Notably, notch ligands were induced in Wnt/beta-catenin activated bone marrow stroma and downstream notch signal activation was seen in the HSCs in contact with the activated stroma. Taken together, Wnt/beta-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