Tissue-specific programming of pericyte-derived mesenchymal stem cells

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间充质干细胞(MSCs)的自然修复过程。驻留在组织中的MSCs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。我们已经证明，在组织损伤后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，在组织损伤时，信号分子被释放，启动了一系列事件，从而刺激周细胞离开血管，增殖(数量增加)，被吸引到损伤部位，然后它们在专门的细胞中分化，介导修复。周细胞作为MSCs来源的吸引力在于它们在血管上无处不在的位置，这意味着它们存在于身体的几乎所有组织中，随时准备被刺激。骨髓间充质干细胞是成体干细胞的重要来源，可用于多种不同的临床应用。目前有150多项临床试验正在进行中，以评估这些细胞的广泛治疗用途。MSCs的主要特征是在实验室培养中被刺激分化为多种不同类型的间充质细胞的能力。这些细胞包括骨细胞。软骨细胞和脂肪细胞等。最近，有证据表明，虽然从不同组织分离的MSCs都来自周细胞，但它们在分化能力上表现出根本的差异。因此，在非刺激性条件下，来自肌肉的MSCs只能形成肌肉细胞，来自骨骼的MSCs只能形成骨细胞。此外，组织移植实验的量化结果表明，来自同一组织内不同解剖位置的MSCs。当移植到其他位置时，骨骼对组织的修复作用不大。这些结果表明，间充质干细胞(周细胞)保留了对其起源的了解，这反过来又影响了它们的行为(前程序)。这在生物学上是有道理的，因为这可能是身体确保MSCs不会分化成错误类型的细胞的一种方式。然而，这对于在组织修复中使用这些细胞具有重要的意义。我们研究的目的是了解这种MSC“编程”的生物学本质，以便能够设计出对细胞进行重新编程的方法，使从一个组织中分离出来的细胞能够用于高效和安全地修复另一个组织。

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.