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

干细胞用于新的疾病治疗还处于初级阶段，显示出巨大的前景，拥有巨大的变革医学的潜力。然而，开发干细胞的全部潜力的一个主要挑战是受到以下因素的限制：(1)缺乏明确的、非动物来源的干细胞生长材料，(2)控制干细胞发育为用于治疗的特定细胞类型(例如。(3)具有良好性能的临床相容和有效支架的生产，用于修复或治疗疾病的移植。在自然界中，特定的细胞类型是由干细胞在局部环境(由许多分子组成的矩阵)中发展而来的，这种环境被称为“小生境”，但人们对这些小生境中的各种控制信号知之甚少。生长表面的化学和物理特性以及添加的蛋白质已经被探索过，但被称为糖胺多聚糖(GAG)的特殊糖(葡聚糖)的作用还没有被探索，特别是一种被称为肝素硫酸酯(HS)的类别，它与血液稀释剂肝素有关。这些是在干细胞利基中发现的一类结构多样化的硫酸盐糖，它们通过调节许多控制细胞生长和发育的蛋白质因子而成为干细胞的主要调节者。我们要解决的关键挑战是证明独特的HS结构--“信号”--可以被用来创造可调的、完全定义的、临床上兼容的基质材料，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一直被开发不足，但现在可以通过整合合成、分析方法和干细胞筛选方面的最新进展来首次解决。我们将建立一个独特的HS化合物文库，并在试验台干细胞应用中筛选它们的活性，即增强骨形成软骨细胞和神经修复细胞的生产。我们希望建立一种战略，为骨科和神经修复创造多模式、‘有利于愈合’的医学生物材料。如果成功，该项目将为特定干细胞类型的产生和控制开辟新的重大机会&建立与临床级别的生物材料制造相兼容的方案，用于各种再生医学应用。

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.