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

With contrasting results recently reported on the effects of b-catenin on hematopoietic stem cells (HSCs), the precise role of Wnt on HSC regulation remains in question. Here, we show that Wnt-b-catenin signaling triggers distinct biological effects on HSCs depending on the target of activation within the hematopoietic microenvironment. Retroviral transduction of a stable form of b-catenin into HSCs caused a loss of competitive repopulating units (CRUs) in a limiting-dilution assay, whereas stabilized b-catenin in stromal cells CRU frequencies of co-cultured HSCs with higher preservation of undifferentiated state and caused enhanced levels of reconstitution in a manner dependent on direct contact between HSC and stroma. The enhancing effect of b-catenin stabilized stroma on HSC was also observed for human HSCs exhibiting higher frequencies of lympho-myeloid repopulating cells after transplantation into NOD/SCID mice. Interestingly, gene expression patterns of Wnt signaling molecules revealed compartmentalization in a manner that canonical Wnt ligands were preferentially expressed in the hematopoietic cells while molecules for reception of the signal such as Frizzled receptors or their co-receptors are preferentially expressed in stromal component, suggesting the role of stromal component as a target of Wnt signals in the niche. Furthermore, b-catenin accumulated selectively in the endosteal stroma of the trabecule region in “stressed” marrows, but not in “steady-state” marrows. Taken together, these results suggest stroma-mediated Wnt signals may function as microenvironmental cues for HSC self-renewal in the stem cell niche.