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.

使用干细胞进行新型疾病治疗的使用尚处于起步阶段，并显示出巨大的前景，具有彻底改变医学的巨大潜力。但是，（1）缺乏定义的，非动物衍生的材料来实现干细胞的全部潜力的主要挑战，（（2）将其发育转化为特定的细胞类型（例如，神经元或骨细胞），以及（3）用于修复临床兼容和有效触发性的有效触发物进行过多的治疗或有效的caffortions进行过渡或进行过渡性的处理或有效的特性。在自然界中，特定细胞类型在局部环境（许多分子的基质）中从干细胞中发展出来，称为“利基”，但是对这些壁ci中的各种控制线索的理解很少。已经探索了生长表面的化学和物理性质以及添加的蛋白质，但没有被探索，但未探索称为糖胺聚糖（GAGS）的专用糖（Glycans）的作用，尤其是与纯糖药物肝素有关的称为乙酰硫酸盐（HS）的类。这些是在干细胞生态位中发现的一类结构多样的硫酸糖，它们是干细胞的主要调节剂，通过调节许多控制细胞生长和发育的蛋白质因子。我们将要解决的主要挑战是表明，可以利用独特的HS结构（“提示”）来创建可调的完全定义和临床兼容的基质材料，作为控制细胞细胞的细胞生长和命运决定的底物。由于研究其结构功能的技术障碍，HS的开发不足，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HS。我们将生成一个独特的HS化合物库，并在测试床干细胞应用中筛选其活性，即增强骨形成软骨细胞的产生以及神经元细胞以进行神经修复。我们希望建立一种为骨科和神经系统修复创建多模式的“亲链”医学生物材料的策略。随着成功，这个项目将为生成和控制特定干细胞类型的主要新机会，并建立与生物材料的临床级制造兼容的协议，以用于多种再生医学应用。