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Polyvalent protein-ligand displays for human endometrial stromal cell and embryonic stem cell adhesion differentiation and proliferation

人子宫内膜基质细胞和胚胎干细胞粘附分化和增殖的多价蛋白配体展示

基本信息

批准号：
BB/D522497/1
负责人：
Christopher Van Der Walle
金额：
$ 55.73万
依托单位：
University of Strathclyde
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FD522497%2F1
关键词：
Polyvalent protein ligand displays human

项目摘要

Organ transplants are sometimes required to replace diseases or dysfunctional tissue but patients must take immune suppressants, which have unpleasant side-effects, to prevent rejection of the transplanted tissue. The aim of this project is to discover ways of getting around this problem by a process called tissue engineering. One of the goals of tissue engineering is to take cells from the patient¿s healthy tissue and expand that tissue in the laboratory (in vitro) for transplantation back into the patient without fear of immune response. In the body cells stick (adhere) to an extracellular matrix composed of proteins which guide the cells development (differentiation) and organisation, which are prerequisites for successful expansion of tissue in tissue engineering. Many cells interact with an extracellular matrix protein called fibronectin. Since a synthetic matrix is required for cell support in the laboratory we need to be able to mimic fibronectin. This is commonly done using a small molecular called RGD derived from fibronectin. However, RGD does not provide the full cell support normally afforded by fibronectin. To overcome this limitation we intend to use fragments of fibronectin which fully interact with cells. These fibronectin fragments will be attached to surfaces in a specific orientation (as viewed from the side) and pattern (as viewed from above). The intended pattern will show clusters of fibronectin fragments evenly distributed across the surface. We will prepare human cells from the tissue lining the womb since these cells grow well and reproducibly in the laboratory. We will incubate the cells with our modified surfaces so that we can study the mechanisms controlling cell adherence and differentiation in the artificial cell supports. We then intend to investigate cell growth in three-dimensions (as would normally occur during the organisation of tissue), making 3D scaffolds by attaching the fibronectin fragments within a gel-like substance. Successful proliferation and differentiation of human cells within the 3D scaffold would be a first step to engineering of many tissue type for use in medicine. An important strategy for tissue engineering is the use of embryonic stem cells, which are unusual in that they have the potential to specialise into any particular cell type (such as heart muscle, skin or endometrium). Stem cells are of value where tissue cannot be taken from the patient for in vitro expansion. They would also allow us to generate tissue that would otherwise have to come from animals for experiments. Our work will study how stem cells, originally derived from mouse embryos, multiply and differentiate on surfaces modified with the fibronectin fragments. These mouse stem cells when grown on gelatine supports (as is normally the case) differentiate into either blood cells, heart cells or cells lining the blood vessels. Our work will therefore look specifically for these types of mature cells under the microscope and genes associated with the different cell types. In this way the impact of fibronectin on the stem cells can be assessed and will represent an important step in defining culture conditions that may be of use in tissue generation.

有时需要器官移植来替换疾病或功能失调的组织，但患者必须服用免疫抑制剂，以防止对移植组织的排斥反应，这种抑制剂具有令人不快的副作用。这个项目的目的是通过一种叫做组织工程的方法来发现解决这个问题的方法。组织工程的目标之一是从患者的健康组织中提取细胞，并在实验室（体外）扩增该组织，以便移植回患者体内，而无需担心免疫反应。在体内，细胞粘附（粘附）于由蛋白质组成的细胞外基质，这些蛋白质指导细胞发育（分化）和组织，这是组织工程中成功扩增组织的先决条件。许多细胞与一种叫做纤连蛋白的细胞外基质蛋白相互作用。由于在实验室中需要合成基质来支持细胞，因此我们需要能够模拟纤连蛋白。这通常是使用一种叫做RGD的小分子从纤连蛋白衍生。然而，RGD不提供通常由纤连蛋白提供的全细胞支持。为了克服这一限制，我们打算使用与细胞完全相互作用的纤连蛋白片段。这些纤连蛋白片段将以特定的方向（从侧面观察）和模式（从上面观察）附着在表面上。预期图案将显示均匀分布在整个表面上的纤连蛋白片段簇。我们将从子宫内膜组织中制备人类细胞，因为这些细胞在实验室中生长良好且可重复。我们将用我们修饰的表面孵育细胞，以便我们可以研究控制人工细胞支持物中细胞粘附和分化的机制。然后，我们打算研究三维细胞生长（通常发生在组织组织过程中），通过将纤连蛋白片段附着在凝胶状物质中来制作3D支架。人类细胞在3D支架内的成功增殖和分化将是工程化许多组织类型用于医学的第一步。组织工程的一个重要策略是使用胚胎干细胞，这是不寻常的，因为它们有潜力专门成为任何特定的细胞类型（如心肌，皮肤或子宫内膜）。干细胞在不能从患者身上取出组织进行体外扩增的情况下具有价值。它们还可以让我们产生组织，否则这些组织必须来自动物用于实验。我们的工作将研究最初来自小鼠胚胎的干细胞如何在用纤连蛋白片段修饰的表面上增殖和分化。这些小鼠干细胞在明胶支持物上生长时（通常情况下）分化为血细胞、心脏细胞或血管内衬细胞。因此，我们的工作将在显微镜下专门寻找这些类型的成熟细胞以及与不同细胞类型相关的基因。以这种方式，纤连蛋白对干细胞的影响可以被评估，并将代表定义可能用于组织生成的培养条件的重要步骤。