Wnt signalling and stem cell mobilisation in tissue injury repair

Wnt信号传导和干细胞动员在组织损伤修复中的作用

• 批准号: MR/K011421/1
• 负责人: Paul Sharpe
• 金额: $ 88.29万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK011421%2F1
• 关键词: Wnt; signalling; stem; cell; mobilisation

When tissues are injured (damaged) the body has to respond very rapidly to prevent blood loss and possible infection. Injury to many tiissues stimulates a process of natural repair that involves stem cells. Stem cells, resident in the tissue receive signals release from damaged cells that stimulates them to divide, migrate towards the damage and then differentiate in specific types of cells needed to repair the damage. Little is currently known about how the different parts of the overall process are activated and co-ordinated to achieve efficient repair of tissue damage. This is however an important area in modern medicine since wounds above crtiical sizes often fail to repair and the effectiveness of repair processes decreases with age. A detailed knowledge of the natural repair processes can thus provide improtant information that can be used to improve tissue repair. We have identified a particular molecular (signalling) process that is activated immediately following tissue injury, in all tissues of all species. This identifies this signalling pathway as of fundamental importance in the initiation of the repair process. We have further shown that a source of stem cells that are mobilised following tissue damage are located on the outside of blood vessels (pericytes) and these cells are able to differentiate into different types of specialised cells needed to repair damage. This suggests that upon tissue damage, signalling molecues are realease that initiate a chain of events whereby stem cells, including pericytes, proliferate (increase in number), are attracted to the site of damge whereupon they differentiate in specilaised cells to mediate repair.The aim of this research project is to learn more about this chain of events and the molecules and cells that take part in the repair process. We will used a highly clinically-relevant tissue as our experimental system, namely teeth, which in common with other tisues and organs, have a natural repair process following damage. When the damage is too great or repair fails, teeth become infected and require extenisve and painful treatment such as root canals. We will use a particualr tooth type that has three different areas where stem cells are located, including pericytes on blood vessels. This will allow us to look at different responses in the same tissue. We are able to injury teeth in animals (mice) and also in culture systems where there is no blood supply, thus enabling us to distinguish the relative contributions of blood vessel cells and other cells to the repair process. Mice also have the advantage of being a well-studied model where many different genetically manipulated strains are available to allow is to mark cells to follow their progress during repair.The overall aim of this project is to learn more about the mechanisms that control a crucially important biological process, tissue repair and in doing so provide the basis for the development of novel clinical approaches to improve tissue repair.

当组织受伤(受损)时，身体必须迅速做出反应，以防止失血和可能的感染。对许多组织的损伤刺激了一个涉及干细胞的自然修复过程。干细胞驻留在组织中，接收受损细胞释放的信号，刺激它们分裂，向损伤迁移，然后在修复损伤所需的特定类型的细胞中分化。目前，对于整个过程的不同部分是如何被激活和协调以实现组织损伤的有效修复，人们知之甚少。然而，这是现代医学中的一个重要领域，因为超过临界尺寸的伤口往往无法修复，修复过程的有效性随着年龄的增长而下降。因此，对自然修复过程的详细了解可以提供可用于改善组织修复的重要信息。我们已经确定了在所有物种的所有组织中，在组织损伤后立即激活的一个特殊的分子(信号)过程。这表明该信号通路在修复过程的启动中具有基本重要性。我们进一步证明，在组织损伤后动员的干细胞来源位于血管(周细胞)的外部，这些细胞能够分化为修复损伤所需的不同类型的专业细胞。这表明，在组织损伤后，信号分子确实会启动一系列事件，从而将包括周细胞在内的干细胞增殖(数量增加)吸引到损伤部位，然后它们在特定的细胞中分化以介导修复。本研究项目的目的是了解更多关于这一事件链以及参与修复过程的分子和细胞。我们将使用一种与临床高度相关的组织作为我们的实验系统，即牙齿，它与其他组织和器官一样，在损伤后有一个自然的修复过程。当损伤太大或修复失败时，牙齿会受到感染，需要延长和痛苦的治疗，如根管。我们将使用一种特殊的牙齿类型，它有三个不同的干细胞区域，包括血管上的周细胞。这将使我们能够观察同一组织中的不同反应。我们能够在动物(小鼠)和没有血液供应的培养系统中损伤牙齿，从而使我们能够区分血管细胞和其他细胞在修复过程中的相对贡献。小鼠也有一个很好的研究模型的优势，在那里可以使用许多不同的基因操纵的菌株来标记细胞，以跟踪它们在修复过程中的进展。这个项目的总体目标是更多地了解控制至关重要的生物过程-组织修复的机制，并在这样做的过程中为开发新的临床方法来改善组织修复提供基础。

项目成果

OFCD syndrome and extraembryonic defects are revealed by conditional mutation of the Polycomb-group repressive complex 1.1 (PRC1.1) gene BCOR.

• DOI: 10.1016/j.ydbio.2020.06.013
• 发表时间: 2020-12-01
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Hamline, Michelle Y.;Corcoran, Connie M.;Wamstad, Joseph A.;Miletich, Isabelle;Feng, Jifan;Lohr, Jamie L.;Hemberger, Myriam;Sharpe, Paul T.;Gearhart, Micah D.;Bardwell, Vivian J.
• 通讯作者: Bardwell, Vivian J.

Perivascular Stem Cells at the Tip of Mouse Incisors Regulate Tissue Regeneration.

• DOI: 10.1002/jbmr.2717
• 发表时间: 2016-03
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Pang YW;Feng J;Daltoe F;Fatscher R;Gentleman E;Gentleman MM;Sharpe PT
• 通讯作者: Sharpe PT

Wnt signaling regulates pulp volume and dentin thickness.

• DOI: 10.1002/jbmr.2088
• 发表时间: 2014-04
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Lim WH;Liu B;Cheng D;Hunter DJ;Zhong Z;Ramos DM;Williams BO;Sharpe PT;Bardet C;Mah SJ;Helms JA
• 通讯作者: Helms JA

Promotion of natural tooth repair by small molecule GSK3 antagonists.

• DOI: 10.1038/srep39654
• 发表时间: 2017-01-09
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Neves VC;Babb R;Chandrasekaran D;Sharpe PT
• 通讯作者: Sharpe PT