Wnt regulation of hematopoietic stem cell development and disease

Hematopoietic stem cells (HSCs) are multipotent stem cells that give rise to all cells of the blood and most immune cells. Due to their capacity for unlimited self-renewal, long-term HSCs replenish the blood and immune cells of an organism throughout its life. HSC development, maintenance, and differentiation are all tightly regulated by cell signaling pathways, including the Wnt pathway. Wnt signaling is initiated extracellularly by secreted ligands which bind to cell surface receptors and give rise to several different downstream signaling cascades. These are classically categorized either β-catenin dependent (BCD) or β-catenin independent (BCI) signaling, depending on their reliance on the β-catenin transcriptional activator. HSC development, homeostasis, and differentiation is influenced by both BCD and BCI, with a high degree of sensitivity to the timing and dosage of Wnt signaling. Importantly, dysregulated Wnt signals can result in hematological malignancies such as leukemia, lymphoma, and myeloma. Here, we review how Wnt signaling impacts HSCs during development and in disease.