Wnt regulation of hematopoietic stem cell development and disease

Abstract

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.

Keywords: Hematopoietic stem cells; Leukemia; Lymphoma; Myeloma; Wnt.

Figure 1.

Hematopoietic stem cell differentiation. Long-term (LT) HSC cells self-renew or repopulate the HSC pool. Short-term (ST) HSCs can differentiate into a common myeloid progenitor cell or a common lymphoid progenitor cell, which further differentiate into blood and immune cells.

Figure 2.

Locations of hematopoietic specification, emergence, expansion, and storage in mice, zebrafish, and fruit fly. Specification, indicated as red dots, in mice and zebrafish occurs in hemogenic endothelium, whereas in fruit fly larvae, specification occurs in the lymph glands. Emergence occurs in the aorta-gonad-mesonephros of mice, in the dorsal aorta of zebrafish, and across the pupa of fruit fly. HSC expansion takes place in the fetal liver of mice, in the caudal hematopoietic tissue of zebrafish, and in hematopoietic pockets across the adult fruit fly.

Figure 3:

Schematic of Wnt signaling pathways with and without the presence of a Wnt ligand. BCD pathway is activated by interaction of Frizzled (Fzd) receptor, lipoprotein related protein (LRP) and the Wnt ligand. The signal leads to nuclear translocation of β-catenin into the nucleus where it binds to lymphoid enhancing factor (LEF)/ T cell factor (TCF) transcription factors, thereby initiating transcription of Wnt target genes. One proposed β-catenin independent (BCI) pathway is initiated by the formation of a Ror2/Ryk-Wnt-Fzd complex. This leads to alterations in Ca²⁺ intracellular levels, impacting the protein kinase C (PKC), calmodullin-dependent protein kinase (CaMK) cascades, or NFAT/AP1 driven gene expression. DKK, Dickkopf; Dsh, Disevelled; GSK3β, Glycogen Synthase Kinase 3β; LSD1, Lysine Specific Demethylase 1; Ryk, receptor-like tyrosine kinase; Sfrp, Secreted frizzled-related protein.