The role of galectins in regulating promyelocytic cell stemness and differentiation

了解调控干细胞自我更新和分化为不同类型细胞的分子机制仍然是生物学中的一个中心挑战。造血干细胞发育的一个功能框架涉及糖基化分子和糖链结合蛋白，如Galectins，它们作为特定的干细胞标记物、细胞分化生物标记物和调节分子。Galectins是一个可溶性的β-半乳糖苷结合蛋白家族，在动物细胞内外分别具有不同的糖依赖和非糖依赖功能。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的中性粒细胞分化过程中，特定Galectins的表达经历了不均匀的变化(刺激和抑制)。这些发现表明，不同的Galectins可能在调节细胞自我更新和细胞分化方面发挥不同的作用。我们还发现，细胞分化与细胞内蛋白质的O-GlcNAc糖基化显著减少有关，O-GlcNAc糖基化控制着蛋白质在细胞内隔室之间的运输和分布。考虑到这些新的发现，我们将阐述Galectins对早幼粒细胞自我更新和分化的调节功能依赖于Galectins在细胞中的定位，这是由O-GlcNAc信号机制驱动的。具体地说，我的研究计划将(1)确定Galectin基因抑制对早幼粒细胞分化和Galectin调节基因表达的影响，(2)检测Galectins在分化的和髓系祖细胞之间的分泌和亚细胞定位的差异，以及(3)确定调节髓系细胞Galectin-12表达的转录机制，作为髓系细胞干细胞的潜在生物标志物。这些发现将使我们能够阐明造血细胞中复杂的Galectin网络重构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。

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.