GlycoMatrix: Engineering Tunable Stem Cell Niches Enhanced with Glycosaminoglycan Instructive Cues

GlycoMatrix：利用糖胺聚糖指导线索增强工程可调谐干细胞生态位

• 批准号: EP/X018776/1
• 负责人: Jeremy Turnbull
• 金额: $ 25.76万
• 依托单位: Keele University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX018776%2F1
• 关键词: GlycoMatrix; Engineering; Tunable; Stem; Cell

The use of stem cells for novel disease treatments is in its infancy and shows great promise, holding huge potential to revolutionize medicine. However, a major challenge for exploiting the full potential of stem cells are the limitations imposed by (1) lack of defined, non-animal-derived materials for growing stem cells, (2) control of their development into specific cell types for treatments (eg. neurons or bone cells), and (3) production of clinically compatible and effective scaffolds with favourable properties for transplanting for repair or disease treatments. In nature specific cell types develop from stem cells in a local environment (a matrix of many molecules) called a "niche", but the full range of controlling cues in these niches are poorly understood. The chemical and physical properties of growth surfaces, along with added proteins, have been explored, but not the role of specialised sugars (glycans) called glycosaminoglycans (GAGs), especially a class called heparan sulfates (HS), which are related to the blood-thinning drug heparin. These are a structurally diverse class of sulphated sugars found in the stem cell niche that are master regulators of stem cells via regulating many protein factors that control cell growth and development. The key challenge we will address is to show that unique HS structures - "cues" - can be exploited to create tunable fully-defined and clinically-compatible matrix materials as substrates to control cell growth and fate decisions by stem cells. HS have been under-exploited due to technical barriers to study of their structure-function, but can now be tackled for the first time by integrating recent advances in synthesis, analytical methods and stem cell screening. We will produce a unique library of HS compounds and screen their activity in test-bed stem cell applications, namely the enhanced production of bone-forming chondrocytes, and neuronal cells for nerve repair. We hope to establish a strategy for creating multimodal, 'pro-healing' medical biomaterials for orthopaedic and neurological repair. With success this project would open up major new opportunities for generation and control of specific stem cell types & establishment of protocols compatible with clinical grade manufacturing of biomaterials for diverse regenerative medicine applications.

干细胞在新型疾病治疗中的应用尚处于起步阶段，并显示出巨大的前景，具有革新医学的巨大潜力。然而，开发干细胞全部潜力的一个主要挑战是：(1)缺乏用于培养干细胞的明确的、非动物来源的材料；(2)控制干细胞发育成用于治疗的特定细胞类型（例如：干细胞）。神经元或骨细胞)，以及(3)生产临床相容和有效的支架，具有良好的移植修复或疾病治疗性能。在自然界中，特定的细胞类型由干细胞在称为“生态位”的局部环境（许多分子的基质）中发育而来，但对这些生态位中的全部控制线索知之甚少。生长表面的化学和物理性质，以及添加的蛋白质，已经被探索，但没有被称为糖胺聚糖（GAGs）的特殊糖（聚糖）的作用，特别是一类被称为硫酸肝素（HS），它与血液稀释药物肝素有关。这些是在干细胞生态位中发现的一种结构多样的硫酸糖，通过调节许多控制细胞生长和发育的蛋白质因子，成为干细胞的主要调节剂。我们将解决的关键挑战是展示独特的HS结构-“线索”-可以被利用来创建可调的完全定义和临床兼容的基质材料，作为基质来控制干细胞的细胞生长和命运决定。由于研究其结构功能的技术障碍，HS一直未得到充分利用，但现在可以通过综合合成，分析方法和干细胞筛选的最新进展首次加以解决。我们将建立一个独特的HS化合物库，并筛选它们在干细胞应用实验台上的活性，即增强骨形成软骨细胞的产生，以及用于神经修复的神经细胞。我们希望建立一种策略，创造多模态，“促进愈合”的医学生物材料，用于骨科和神经修复。如果成功，该项目将为特定干细胞类型的产生和控制开辟重要的新机会，并建立与各种再生医学应用的临床级生物材料制造兼容的协议。