The role of galectins in regulating promyelocytic cell stemness and differentiation

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Understanding the molecular mechanisms that regulate self-renewal of stem cells and their differentiation into different cell types remains a central challenge in biology. One functional framework of hematopoietic stem cell development involves glycosylated molecules and glycan-binding proteins, such as galectins, which serve as specific stem cell markers, cell differentiation biomarkers, and regulatory molecules. Galectins are a family of soluble beta-galactoside-binding proteins with diverse glycan-dependent and glycan-independent functions outside and inside the animal cell, respectively. We have recently demonstrated that the expression of specific galectins undergoes non-uniform changes (stimulation versus inhibition) during neutrophilic differentiation in a model of promyelocytic HL-60 stem-like progenitor cells. These findings indicate that individual galectins may play different roles in regulating cell self-renewal and cell differentiation. We also have shown that the cell differentiation is associated with a significant decrease of global O-GlcNAc glycosylation of intracellular proteins that controls protein trafficking and distribution between intracellular compartments. Considering these novel findings, we will elaborate the hypothesis that regulatory functions of galectins toward self-renewal and differentiation of promyeloid cells depends on the localization of galectins in cells which is driven by O-GlcNAc signaling mechanisms. Specifically, my research program will (1) determine the consequences of galectin gene inhibition on promyelocytic cell differentiation and the expression of galectin-regulated genes, (2) examine variations in secretion and subcellular localization of the galectins between differentiated and myeloid progenitor cells, and (3) determine transcriptional mechanisms regulating galectin-12 expression in myeloid cells as a potential biomarker of promyeloid cell stemness. These findings will allow us to elucidate the biological significance and necessity of the complex galectin network remodeling in hematopoietic cells. This knowledge can be translated into novel approaches to control cell self-renewal, proliferation, survival, and differentiation that are essential themes central to developmental biology, tissue regeneration and bioengineering.