Epigenetic modulation of Wnt signalling in the ageing human intestinal epithelium: consequences for tissue homeostasis

人类的肠道里布满了被称为隐窝的指状内陷，它在不断地更新。每个隐窝由来自存在于每个隐窝基部的少量干细胞的细胞填充。干细胞通常不对称地分裂以产生一个干细胞和一个子细胞，从而维持干细胞群体。子细胞在向地穴一侧移动的同时对称地分裂多次，直到大约一半时停止分裂并分化成正常肠道功能所需的几种细胞类型之一。这些细胞成为肠道表面的组成部分，在那里它们被编程死亡，并被排入粪便流。细胞分裂、迁移和分化的速率由几个基因的表达非常严格地控制。我们之前已经证明，控制细胞分裂，迁移和分化的几个基因在衰老的人类肠道中通过向包含这些基因的DNA序列中添加甲基而逐渐关闭。由于肠道内衬有隐窝，其中所有细胞都来源于少量干细胞，因此干细胞的任何变化，如基因甲基化，都会传递给其所有后代，并将代表隐窝内细胞群体的重要比例。这意味着这些基因被关闭的细胞不会均匀分布在整个肠道中，而是定位于特定的隐窝，导致受影响的隐窝的马赛克模式，最终可能会增加疾病的风险。我们以前发现这在老年受试者中是真实的。在这里，我们的目标是将这些观察扩展到更多不同年龄的人，以确定是否像我们预测的那样，在衰老过程中，越来越多的这些重要基因被甲基化关闭，并且这种情况发生在越来越多的隐窝中。我们还旨在了解当这些重要基因在干细胞中关闭时，隐窝中会发生什么。细胞分裂得更快吗？它们在分裂的同时会继续往上走吗？这些细胞是否更有可能或更少地分化成一种细胞或另一种细胞？它们对程序性细胞死亡的抵抗力更强吗？这些问题的答案可能有助于我们了解衰老过程中出现的问题，并可能为预防与年龄有关的疾病提供策略。

The human gut, which is lined with finger-like invaginations called crypts, is continually being renewed. Each crypt is populated by cells derived from a small number of stem cells present at the bases of each crypt. The stem cells usually divide asymmetrically to produce one stem cell and one daughter cell, thus maintaining the stem cell population. The daughter cell divides symmetrically several more times while moving up the side of the crypt until, about halfway up, it stops dividing and differentiates into one of several cell types necessary for normal gut function. These cells become components of the gut surface, where they are programmed to die, and are shed into the faecal stream. The rates of cell division and migration and differentiation are very tightly controlled by the expression of several genes. We have previously shown that several of the genes controlling cell division, migration and differentiation are gradually switched off in the ageing human gut by the addition of methyl groups to the DNA sequences comprising these genes. Since the gut is lined with crypts, where all cells are derived from a small number of stem cells, any change to a stem cell, such as gene methylation, will be passed on to all its progeny and will represent a significant proportion of the population of cells within the crypt. This implies that cells in which these genes are switched off will not be uniformly distributed throughout the gut, but rather they will be localised to specific crypts, resulting in a mosaic pattern of affected crypts that may eventually be at increased risk of disease. We have previously found this to be true in elderly subjects. Here we aim to extend these observations to many more people of different ages, to determine if, as we predict, during ageing more and more of these important genes are switched off by methylation, and that this occurs in increasing numbers of crypts. We also aim to understand what happens in the crypts when these important genes are switched off in the stem cells. Do the cells divide more rapidly? Do they travel further up the crypt while still dividing? Are the cells more or less likely to differentiate into one type of cell or another? Are they more resistant to programmed cell death? The answers to these questions may help us to understand what is going wrong during the ageing process, and may provide insight into strategies for the prevention of age-related disease.