Universal cells to overcome HLA barriers in regenerative medicine

克服再生医学中 HLA 障碍的通用细胞

• 批准号: MR/S02090X/1
• 负责人: Waseem Qasim
• 金额: $ 106.52万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS02090X%2F1
• 关键词: Universal; cells; overcome; HLA; barriers

Over 6400 people are waiting for solid organ transplants in the UK and one major issue is the need to match donors and recipients to prevent the immune system rejection. Recent developments suggest that 'genome editing' might allow us to produce 'universal' stem cells that can be used to repair or regenerated diseased organs. We are interested in applying the technology to pluripotent stem cells that could then be used to generate many different types of tissue. The process involves using tools called CRISPR-Cas9 to change the cells' DNA to make them cells invisible to the immune system. This is done by disrupting the DNA code in cells that produces surface molecules called human leukocyte antigens (HLA). These are like 'flags' that identify cells as host or 'self' and each cell can display up to 12 different very different flags from two different classes or structures.The project will tests strategies to remove the flags. It may be neccessary to replace them with a single 'neutral' flag in case the immune system becomes alarmed that all the flags are missing. We will compare different routes to efficiently and safely manufacture 'universal cells' which will then be tested in projects already underway in the regenerative medicine hubs. In case of unwanted side effects, a safety gene will also be included to allow cells to be removed if necessary.We will deliver the project in four stages with the bulk of the first stages to be undertaken at UCL and UoC. There is additional involvement of UKRMP hubs in Edinburgh and Cambridge in the final year. Four 'work packages are envisaged:1. To develop and test the molecular tools that will be used to cut and edit DNA that codes for 'flags' on cells2. Test and grow human 'stem' cells that can be later used to produce large numbers of liver cells or immune cells that help clean up cell debris. The tools developed in (1) will be used to modify these stem cells in the lab to see if they can be made 'universal' 3. Apply state of the art sequencing and computer modelling to check if the stem cells have been modified at gene sites other than those being targeted.4. Testing the inclusion of a 'safety' switch in case cells cause side effects or get infected with viruses.5. Testing of universal stem cells to see if they can evade immune responses in mice.By the end of the project, we anticipate being in a position to be able to produce 'universal' pluripotent stem cells that could then be applied to various applications in early stage clinical trials.

在英国，有超过6400人在等待实体器官移植，其中一个主要问题是需要匹配捐赠者和接受者，以防止免疫系统排斥。最近的发展表明，“基因组编辑”可能使我们能够产生可用于修复或再生患病器官的“通用”干细胞。我们有兴趣将这项技术应用于多能干细胞，然后可以用来产生许多不同类型的组织。该过程涉及使用称为CRISPR-Cas9的工具来改变细胞的DNA，使它们对免疫系统不可见。这是通过破坏细胞中产生称为人类白细胞抗原（HLA）的表面分子的DNA代码来实现的。这些就像“标志”，将细胞识别为宿主或“自身”，每个细胞可以显示多达12个不同的标志，这些标志来自两个不同的类或结构。该项目将测试删除标志的策略。如果免疫系统发现所有的标记都丢失了，那么用一个“中性”标记来代替它们可能是必要的。我们将比较不同的路线，以有效和安全地制造“通用细胞”，然后将在再生医学中心正在进行的项目中进行测试。如果出现不必要的副作用，还将包括一个安全基因，以便在必要时去除细胞。我们将分四个阶段交付该项目，第一阶段的大部分将在UCL和UoC进行。在最后一年，爱丁堡和剑桥的UKRMP中心也参与其中。设想了四个“工作包”：1.开发和测试分子工具，用于切割和编辑细胞上编码“标志”的DNA。测试和培养人类“干”细胞，这些细胞以后可以用来产生大量的肝细胞或免疫细胞，帮助清理细胞碎片。在（1）中开发的工具将用于在实验室中修改这些干细胞，看看它们是否可以被“通用”。应用最先进的测序和计算机建模技术来检查干细胞是否在靶基因位点以外的基因位点被修饰。测试包含一个“安全”开关，以防细胞引起副作用或感染病毒。测试通用干细胞，看看它们是否可以逃避小鼠的免疫反应。到项目结束时，我们预计能够生产出“通用”多能干细胞，然后可以在早期临床试验中应用于各种应用。

项目成果

The Microfluidic Environment Reveals a Hidden Role of Self-Organizing Extracellular Matrix in Hepatic Commitment and Organoid Formation of hiPSCs.

• DOI: 10.1016/j.celrep.2020.108453
• 发表时间: 2020-12-01
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Michielin F;Giobbe GG;Luni C;Hu Q;Maroni I;Orford MR;Manfredi A;Di Filippo L;David AL;Cacchiarelli D;De Coppi P;Eaton S;Elvassore N
• 通讯作者: Elvassore N