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Keywords:

  • Hematopoietic stem cell;
  • Self-renewal;
  • Wnt;
  • Stroma;
  • Stem cell–microenvironment interactions

Abstract

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