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.

使用干细胞治疗新型疾病尚处于起步阶段，并显示出巨大的前景，具有彻底改变医学的巨大潜力。然而，充分利用干细胞潜力的一个主要挑战是以下因素所带来的限制：(1) 缺乏用于生长干细胞的明确的非动物源性材料，(2) 控制它们发育成用于治疗的特定细胞类型。 (例如神经元或骨细胞)，以及(3)生产具有良好移植修复或疾病治​​疗特性的临床相容且有效的支架。在自然界中，特定的细胞类型是从称为“生态位”的局部环境（许多分子的基质）中的干细胞发育而来的，但人们对这些生态位中的全部控制线索知之甚少。人们已经探索了生长表面以及添加的蛋白质的化学和物理特性，但尚未探索称为糖胺聚糖 (GAG) 的特殊糖（聚糖）的作用，尤其是与血液有关的硫酸类肝素 (HS) -稀释药物肝素。这些是在干细胞生态位中发现的一类结构多样的硫酸化糖，它们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。我们要解决的关键挑战是证明独特的 HS 结构（“线索”）可用于创建可调节的完全定义且临床兼容的基质材料，作为控制细胞生长和干细胞命运决定的基质。由于研究其结构功能的技术障碍，HS 一直未被充分利用，但现在可以通过整合合成、分析方法和干细胞筛选的最新进展来首次解决该问题。我们将生产一个独特的 HS 化合物库，并在试验台干细胞应用中筛选它们的活性，即增强成骨软骨细胞和用于神经修复的神经元细胞的生产。我们希望制定一项战略，为骨科和神经系统修复创造多模式、“促进愈合”的医用生物材料。如果该项目取得成功，将为特定干细胞类型的生成和控制以及建立与各种再生医学应用的生物材料的临床级制造兼容的协议开辟重大新机会。