Dammen-Brower Kris, Arbogast Olivia, Zhu Stanley, Qiu Chunfang, Zhang Cissy, Khare Pratik, Le Anne, Jia Xiaofeng, Yarema Kevin J
Department of Biomedical Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Whiting School of Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
Biomater Adv. 2025 Apr;169:214144. doi: 10.1016/j.bioadv.2024.214144. Epub 2024 Dec 7.
This study defines biochemical mechanisms that contribute to novel neural-regenerative activities we recently demonstrated for thiol-modified ManNAc analogs in human neural stem cells (hNSCs) by comparing our lead drug candidate for brain repair, "TProp," to a "size-matched" N-alkyl control analog, "But." These analogs biosynthetically install non-natural sialic acids into cell surface glycans, altering cell surface receptor activity and adhesive properties of cells. In this study, TProp modulated sialic acid-related biology in hNSCs to promote neuronal differentiation through modulation of cell adhesion molecules (integrins α6, β1, E-cadherin, and PSGL-1) and stem cell markers. By comparison, But elicited minimal change to these endpoints, indicating dependence on the chemical properties of the thiol group of non-natural sialic acids and not the size of this sugar's N-acyl group. Conversely, But elicited distinct intracellular responses including increased nestin expression (~6-fold) and the modulation of several metabolites identified through cell-wide screening. Metabolites up-regulated by But included dopamine and norfenenfrine, suggesting that this analog may be a drug candidate for treating neural damage associated with conditions such as Parkinson's disease. The metabolomics data also provided new insights into the neuroprotective effects of TProp when used to treat brain injury by upregulation of anti-inflammatory metabolites (e.g., α- & γ-linolenic acids) valuable for dampening injury- and treatment-related inflammation. Finally, these analogs modulate compounds that control proline (e.g., 1-pyrroline-2-carboxylate), a master regulator of many cellular activities. Overall, this study presents new mechanisms and pathways to exploit metabolic glycoengineering for neural repair and treatment of neurodegenerative diseases.
本研究通过将我们用于脑修复的先导候选药物“TProp”与“大小匹配”的N-烷基对照类似物“But”进行比较，确定了有助于我们最近在人类神经干细胞（hNSCs）中证明的硫醇修饰的甘露糖胺类似物具有新型神经再生活性的生化机制。这些类似物通过生物合成将非天然唾液酸安装到细胞表面聚糖中，改变细胞表面受体活性和细胞的粘附特性。在本研究中，TProp调节hNSCs中与唾液酸相关的生物学过程，通过调节细胞粘附分子（整合素α6、β1、E-钙粘蛋白和PSGL-1）和干细胞标志物来促进神经元分化。相比之下，But对这些终点的影响极小，表明其依赖于非天然唾液酸硫醇基团的化学性质，而非该糖N-酰基的大小。相反，But引发了不同的细胞内反应，包括巢蛋白表达增加（约6倍）以及通过全细胞筛选鉴定的几种代谢物的调节。But上调的代谢物包括多巴胺和去甲肾上腺素，表明该类似物可能是治疗与帕金森病等疾病相关的神经损伤的候选药物。代谢组学数据还为TProp用于治疗脑损伤时的神经保护作用提供了新的见解，即通过上调对减轻损伤和治疗相关炎症有价值的抗炎代谢物（如α-和γ-亚麻酸）。最后，这些类似物调节控制脯氨酸的化合物（如1-吡咯啉-2-羧酸盐），脯氨酸是许多细胞活动的主要调节因子。总体而言，本研究提出了利用代谢糖工程进行神经修复和治疗神经退行性疾病的新机制和途径。
