The role of galectins in regulating promyelocytic cell stemness and differentiation

半乳糖凝集素在调节早幼粒细胞干细胞分化中的作用

• 批准号: RGPIN-2019-06628
• 负责人: Timoshenko, Alexander
• 金额: $ 2.33万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745915
• 关键词: role; galectins; regulating; promyelocytic; cell

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.

了解调节干细胞自我更新及其分化为不同细胞类型的分子机制仍然是生物学的核心挑战。造血干细胞发育的一个功能框架涉及糖基化分子和聚糖结合蛋白，如半乳糖凝集素，其用作特异性干细胞标志物、细胞分化生物标志物和调节分子。半乳糖凝集素是一类可溶性β-半乳糖苷结合蛋白，在动物细胞内外分别具有不同的聚糖依赖性和聚糖非依赖性功能。我们最近已经证明，在早幼粒细胞HL-60干细胞样祖细胞模型中，特定半乳糖凝集素的表达在嗜中性粒细胞分化过程中经历了不均匀的变化（刺激与抑制）。这些发现表明，个别半乳糖凝集素可能在调节细胞自我更新和细胞分化中发挥不同的作用。我们还表明，细胞分化与细胞内蛋白质的整体O-GlcNAc糖基化的显著降低有关，所述糖基化控制细胞内区室之间的蛋白质运输和分布。考虑到这些新的发现，我们将阐述的假设，半乳糖凝集素对自我更新和分化的早幼粒细胞的调节功能取决于半乳糖凝集素在细胞中的定位，这是由O-GlcNAc信号传导机制驱动。具体来说，我的研究计划将（1）确定半乳糖凝集素基因抑制对早幼粒细胞分化和半乳糖凝集素调节基因表达的影响，（2）检查分化和髓系祖细胞之间半乳糖凝集素分泌和亚细胞定位的变化，和（3）确定调节骨髓细胞中半乳糖凝集素-12表达的转录机制作为早幼粒细胞干细胞性的潜在生物标志物。这些发现将使我们能够阐明造血细胞中复杂的半乳凝素网络重塑的生物学意义和必要性。这些知识可以转化为控制细胞自我更新，增殖，存活和分化的新方法，这些都是发育生物学，组织再生和生物工程的核心主题。