Dynamic surfaces to mimic mesenchymal stem cell niche functions

我们生活在一个老龄化的社会，我们的身体已经超出了有用的寿命。结构部件患有关节炎或骨质疏松症，器官提供的效率降低，并可能因退化过程而受损或患病。我们生活在历史上一个激动人心的时刻，我们都期望释放干细胞的潜力将有助于满足这些紧迫的再生需求。然而，胚胎干细胞仍然处于伦理争论之中，而且还存在与其使用相关的临床问题(包括缺乏免疫特免权，这可能会导致不良免疫反应，以及可能形成畸胎瘤，这是癌症的一种)。成人干细胞提供了另一种途径，例如来自骨髓(例如通过骨髓捐赠获得的)或来自脂肪组织(例如通过吸脂获得)的间充质干细胞提供了一个有吸引力的、自体(即来自患者)的多潜能细胞来源。成体干细胞的一个主要障碍是它们在实验室标准培养期间的快速和自发分化(即它们在体外迅速停止作为干细胞的作用)。目前的细胞培养材料是在我们对干细胞的了解成熟之前开发的，旨在培养成熟的细胞类型(如成纤维细胞)或细胞系(如HeLa细胞)。因此，我们目前缺乏良好的自体干细胞生长平台。在过去的几年里，包括我们自己在内的研究人员已经了解到，MSC的生长和分化受到细胞附着材料的方式的控制，开始出现一致的规则。然而，材料科学的发展提出了有利于骨髓间充质干细胞生长或有利于分化的表面，但这两种表面都无法控制。在我们的体内，干细胞驻留在特定的位置(称为“壁龛”)，这些位置控制着它们的生长，使干细胞的供应能够在我们的一生中存在于组织中，并根据组织需求调节分化。同样，细胞黏附是干细胞生态位调节的关键。在这里，我们将开发高度新颖的材料，最初支持多潜能MSCs的生长(增殖)，然后可以在用户控制下切换以开启所需类型的分化，以生成人体成熟的功能细胞。为此，我们将使用酶(生物催化剂)裂解自我更新表面(这将通过使用黏附控制化学和利用纳米级空间信息，即小的化学模式)，并揭示潜在的分化表面(不同的化学物质控制差异黏附，从而决定干细胞的命运)。这种酶可以由使用者简单地添加到细胞培养基中(他们的食物)。然后，我们将更进一步，将交换机置于单元控制之下。随着细胞在培养中变得密集(接近融合)，它们的蛋白质(从而酶)谱会发生变化，我们将利用这一点来寻找只有在细胞大量生长后才能从促进生长的底物切换到诱导分化的底物的酶。这项技术将作为MSC生长和分化的平台。这将是动态的，因为它们的自然生态位是动态的，这将是生产具有治疗潜力的自体细胞的重要一步。

We live in an ageing society and we are outliving the useful lives of our bodies. Structural components suffer with arthritis or osteoporosis and organs provide reduced efficiency and can become damaged or diseased through degenerative processes. We live at an exciting point in history where we all have the expectation that unlocking the potential of stem cells will help with these urgent regenerative demands. Embryonic stem cells remain locked in ethical debate, however, and also have clinical issues associated with their use (including lack of immune privilege, which can cause adverse immune reactions, and the possibility of teratoma formation, which is a type of cancer ). Adult stem cells provide an alternate route with mesenchymal stem cells from, for example, bone marrow (obtained by e.g. marrow donation) or fat tissue (obtained by e.g. liposuction) providing an attractive, autologous (i.e. from the patient) source of multipotent cells. A major hurdle with adult stem cells is their rapid and spontaneous differentiation during standard culture in the lab (i.e. out of the body they rapidly stop acting as stem cells). Current cell culture materials were developed before our understanding of stem cells had matured and were designed to grow mature cell types (such as fibroblasts) or cell lines (such as HeLa cells). Thus, we are currently lacking good platforms for autologous stem cell growth.In the last few years, researchers, including ourselves, have understood that MSC growth and differentiation is controlled by the way cells adhere to materials and consistent 'rules' are starting to emerge. Developments in materials science have put forwards surfaces that are either favourable for MSC growth or good for differentiation, however, but that cannot control both.In our bodies, stem cells reside in specialised locations (called 'niches') that control their growth to allow a supply of stem cells to be present in tissues throughout our lives and also regulate differentiation in response to tissue demand. It is, again, considered that cell adhesion is key to the niche regulation of stem cells.Here, we will develop highly novel materials that initially support the growth (multiplication) of multipotent MSCs, which can then be switched under user control to turn on the desired type of differentiation, to generate the mature 'functional' cells of the body. To do this, we will use enzymes (biological catalysts) to cleave the self-renewal surface (this will be made by use of adhesion controlling chemistry and use of nanoscale spatial information i.e. small chemical patterns) and reveal the underlying differentiation surface (different chemistries to control differential adhesion, and hence drive stem cell fate). Such enzymes can be simply added by the user to the cell media (their food). We will then go further and place the switch under cell control. As cells become dense in a culture (near confluence) their protein (and hence enzyme) profile changes and we will exploit this to find enzymes that can perform the switch from a growth-promoting substrate to a differentiation-inducing substrate, only after the cells have grown to large numbers.This technology will act as a platform for MSC growth and differentiation. It will be dynamic, as their natural niche is dynamic, and it will be an important step in the development of production of autologous cells with therapeutic potential.