Effect of the topography of the human epidermal-dermal junction in influencing stem cell behaviour

表皮是皮肤的外层覆盖物，在保护我们的身体免受细菌和其他病原体的侵袭方面起着至关重要的作用。它是由堆叠在一起的多层电池组成的。最深的细胞层，离皮肤表面最远，含有干细胞。它们的作用是在我们的一生中进行分裂，使更多的细胞随后在穿过上层细胞层时成熟。最成熟的细胞专门在皮肤表面形成一道保护性屏障。如果从体内取出一小块皮肤并将其带到实验室，就有可能长出与正常表皮具有相似特性的表皮，事实上，这些表皮可以用来修复烧伤和其他类型的皮肤伤口。人类表皮的一个有趣特征是，干细胞聚集在基底细胞层的特定位置，这与表皮和底层结缔组织之间的边界上的自然波动有关。随着年龄的增长，波纹变得不那么明显，但相比之下，在一些常见的皮肤病中，如牛皮癣，波纹变得更加突出。我们想要了解为什么干细胞以这种方式聚集，以及波动的大小是否会影响它们的行为。为了研究这一点，我们将在由人造材料制成的特殊表面上培养人类表皮细胞，例如用作浴缸密封剂的橡胶物质，以重建波纹。我们将测量这些表面不同位置的细胞是更有可能作为干细胞保留下来，还是更有可能离开基底层并成熟。我们将研究在类似老化皮肤的基质上，细胞是否显示出分裂和成熟的改变能力。我们将通过识别干细胞内发生的信号事件来发现底物如何指导干细胞的行为。我们还将探索是否可以通过人为刺激细胞内基因表达的变化来超越底物的影响。该项目的结果将首次解释为什么干细胞位于人类表皮的特定位置，以及它们所在位置提供的信息是否有助于与皮肤老化有关的表皮变化。

The epidermis is the outer covering of the skin and plays an essential role in protecting our bodies from bacteria and other pathogens. It is made up of multiple layers of cells that are stacked on top of one another. The deepest cell layer, furthest from the skin surface, contains stem cells. Their role is to divide throughout our lives to make more cells that subsequently mature as they move through the upper cell layers. The most mature cells are specialised to form a protective barrier on the skin surface. If a tiny piece of skin is removed from the body and taken to the laboratory, it is possible to grow sheets of epidermis that have similar properties to normal epidermis and indeed these sheets can be used to repair burns and other types of skin wound. One interesting feature of human epidermis is that the stem cells are clustered in specific positions in the basal cell layer, which correlate with natural undulations in the boundary between the epidermis and the underlying connective tissue. As we age the undulations become much less pronounced, but in contrast in some common skin diseases such as psoriasis the undulations become more prominent. We would like to understand why the stem cells are clustered in this way and whether the size of the undulations affects their behaviour. To investigate this we will grow human epidermal cells on special surfaces made out of artificial materials, such as the rubbery substance used as bath sealant, that recreate the undulations. We will measure whether cells in different positions on these surfaces are more likely to remain as stem cells or to leave the basal layer and mature. We will investigate whether on substrates that resemble aged skin the cells show an altered ability to divide and mature. We will discover how the substrates direct the stem cells to behave by identifying the signalling events that take place inside the stem cells. We will also find out whether we can over-ride the effects of the substrates by artificially stimulating changes in gene expression inside the cells.The outcome of the project will be to explain, for the first time, why stem cells lie in specific locations in human epidermis and whether the information provided by their location contributes to the changes in the epidermis that are linked to skin ageing.