Tissue-specific programming of pericyte-derived mesenchymal stem cells

周细胞来源的间充质干细胞的组织特异性编程

• 批准号: MR/K018035/1
• 负责人: Paul Sharpe
• 金额: $ 61.78万
• 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%2FK018035%2F1
• 关键词: Tissue; specific; programming; pericyte; derived

When tissues are injured (damaged) the body has to respond very rapidly to prevent blood loss and possible infection. Injury to many tissues stimulates a process of natural repair that involves mesenchymal stem cells (MSCs). MSCs resident in the tissue receive signals released 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. We have shown that a source of stem cells that are mobilised following tissue damage are located on the outside of blood capillaries (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 released that initiate a chain of events whereby pericytes are stimulated to leave the blood vessels, proliferate (increase in number), are attracted to the site of damage whereupon they differentiate in specialised cells to mediate repair. The attraction of pericytes as a source of MSCs is their ubiquitous location on blood vessels that means they are present in almost all tissues of the body, ready to be stimulated. MSCs are an important source of adult stem cells for use in many different clinical applications. There are currently over 150 clinical trails underway to evaluate these cells for a wide range of therapeutic uses. The main defining characteristic of MSCs is their ability to differentiate into multiple different types of mesenchymal cells when stimulated to do so in laboratory cultures. These include, bone cells. cartilage cells and fat cells among others. Recently, evidence has started to emerge that suggests that although MSCs isolated from different tissues are all derived from pericytes, they exhibit fundamental differences in their differentiation capacities. Thus when grown in non-stimulatory conditions, MSCs from muscle will only form muscle cells and MSCs from bone will only form bone cells. Moreover, tantilising results from tissue transplantation experiments suggest that MSCs from different anatomical sites within one tissue, eg. bone, are inaffective at repairing the tissue when transplantated to the other location. These results suggest that MSCs (pericytes) retain a knowledge of their origin that in turn affects their behaviour (pregramme). This makes biological sense since it may be a way of the body ensuring that MSCs dont differentiate into the wrong type of cell. However it has important implications for using these cells in tissue repair.The aim of our research is to understand the biological nature of this MSC "programming" so that ways can be devised to reprogramme the cells to enable cells isolated from one tissue can be used to efficiently and safely repair another tissue.

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。许多组织的损伤刺激了一个涉及间充质干细胞（MSCs）的自然修复过程。驻留在组织中的间充质干细胞接收受损细胞释放的信号，刺激它们分裂，向受损部位迁移，然后分化为修复损伤所需的特定类型的细胞。我们已经证明，组织损伤后被动员的干细胞来源位于毛细血管（周细胞）的外部，这些细胞能够分化成修复损伤所需的不同类型的专门细胞。这表明，在组织损伤时，信号分子被释放，引发一系列事件，其中周细胞被刺激离开血管，增殖（数量增加），被吸引到损伤部位，然后它们在特化细胞中分化以介导修复。周细胞作为间充质干细胞来源的吸引力在于它们在血管上无处不在，这意味着它们几乎存在于身体的所有组织中，随时准备受到刺激。间充质干细胞是成体干细胞的重要来源，可用于许多不同的临床应用。目前有超过150项临床试验正在进行中，以评估这些细胞的广泛治疗用途。间充质干细胞的主要特征是在实验室培养的刺激下，它们能够分化成多种不同类型的间充质细胞。这些包括骨细胞。软骨细胞和脂肪细胞等等。最近，有证据表明，虽然从不同组织中分离的间充质干细胞都来源于周细胞，但它们的分化能力存在根本差异。因此，在非刺激条件下生长时，来自肌肉的间充质干细胞只会形成肌肉细胞，而来自骨骼的间充质干细胞只会形成骨细胞。此外，组织移植实验的tantilising结果表明，来自一个组织内不同解剖部位的MSCs，例如：当骨移植到其他部位时，对组织的修复是无效的。这些结果表明MSCs（周细胞）保留了其起源的知识，这反过来影响了它们的行为（程序）。这在生物学上是有意义的，因为这可能是身体确保间充质干细胞不会分化成错误类型细胞的一种方式。然而，它对利用这些细胞进行组织修复具有重要意义。我们研究的目的是了解这种MSC“编程”的生物学性质，以便设计出重新编程细胞的方法，使从一个组织分离的细胞能够有效和安全地用于修复另一个组织。

项目成果

Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor.

• DOI: 10.1016/j.stem.2013.12.013
• 发表时间: 2014-02-06
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Zhao, Hu;Feng, Jifan;Seidel, Kerstin;Shi, Songtao;Klein, Ophir;Sharpe, Paul;Chai, Yang
• 通讯作者: Chai, Yang

A quiescent cell population replenishes mesenchymal stem cells to drive accelerated growth in mouse incisors.

静止的细胞种群补充间充质干细胞以驱动小鼠切牙的加速生长。

• DOI: 10.1038/s41467-017-02785-6
• 发表时间: 2018-01-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: An Z;Sabalic M;Bloomquist RF;Fowler TE;Streelman T;Sharpe PT
• 通讯作者: Sharpe PT

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