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An evolutionarily restricted role for purinergic signalling in the maintenance of retinal stem cells

嘌呤能信号在视网膜干细胞维持中的进化限制作用

基本信息

批准号：
BB/I013636/1
负责人：
Rachael Pearson
金额：
$ 53.35万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI013636%2F1
关键词：
evolutionarily restricted role purinergic signalling

项目摘要

During embryogenesis the eye is formed by a highly organized and stereotyped pattern of events, in which retinal progenitor cells divide (proliferate) many times before exiting the cell cycle and forming the different neuronal cell types of the adult retina in a process called differentiation. Once formed, the mammalian eye is thought to be incapable of regeneration. Thus, any loss of retinal cells, including the light-sensitive photoreceptors, either by disease or injury during life is permanent. In contrast, the eye of lower vertebrates, such as fish and frogs, continues to grow throughout the life of the animal. New retinal neurons, including photoreceptors, are produced by the proliferation of a population of stem cells that reside in a region called the ciliary marginal zone (CMZ), at the very periphery of the retina. Over the past decade, there has been significant interest in the possibility of retinal repair in humans following the discovery of a population of cells within the ciliary epithelium (CE), found within the ciliary body of the mammalian eye, a region analogous to the lower vertebrate CMZ. These cells exhibit a number of stem cell-like properties, although it is not yet clear if these cells can go on to form all the cell types of the retina. More importantly, these cells only proliferate when cultured in a dish - they are dormant in the eye itself. This raises the question of whether these cells represent a population of stem cells that are similar to those found in frogs and fish but that have lost the capacity for proliferation and repair during evolution. Furthermore, it is conceivable that these cells could be reactivated to generate new retinal neurons. The mechanisms that regulate both the proliferation of the stem cells in the lower vertebrate and the apparent dormancy of this stem cell-like population in mammals are poorly understood. Recently, one signalling pathway, called purinergic signalling, has been shown to be essential for turning on a number of genes required for eye formation. We have also shown that this signalling mechanism is very important for controlling the proliferation of retinal progenitor cells in the early stages of eye development in the embryo. Here, we aim to determine whether or not purinergic signalling represents a fundamental regulatory mechanism that controls the proliferation of retinal stem cells at the ciliary margin. Moreover, we wish to determine whether or not this signalling system has become lost or restricted during evolution and so provide an explanation for why the stem cells of the mammalian CE no longer proliferate. We have already found that purinergic signalling is involved in the proliferation of mammalian retinal stem cells in the culture dish. We have also found that a particular type of receptor that is critical for purinergic-mediated proliferation elsewhere in the brain is not present in the mammalian CE, but is found in these cells when they are cultured in the dish. This means it may be possible to induce the normally dormant stem cells of the mammalian eye to proliferate and form new retinal neurons in the eye. Therefore, we aim to firstly examine the role of purinergic signalling in controlling retinal stem cell proliferation both in the adult eye and in the culture dish. We will also determine the downstream pathway of purinergic signalling that leads to this proliferation. We will compare evolutionarily distinct species to examine the role of purinergic signalling in the retina of these animals and finally we will determine whether or not it is possible to reactivate the stem cells of the mammalian CE by purinergic signalling. Although only theoretical at this point, it is possible that the last objective may provide information for the repair of the retina damaged through disease or injury.

在胚胎发生期间，眼睛是由高度组织化和定型的事件模式形成的，其中视网膜祖细胞在退出细胞周期之前分裂（增殖）多次，并在称为分化的过程中形成成人视网膜的不同神经元细胞类型。一旦形成，哺乳动物的眼睛被认为是无法再生的。因此，视网膜细胞的任何损失，包括光敏感的光感受器，无论是在生活中的疾病或损伤是永久性的。相比之下，低等脊椎动物的眼睛，如鱼和青蛙，在动物的一生中不断生长。新的视网膜神经元，包括光感受器，是由一群干细胞的增殖产生的，这些干细胞位于视网膜最外围的睫状边缘区（CMZ）。在过去的十年中，在发现睫状上皮（CE）内的细胞群之后，人们对人类视网膜修复的可能性产生了极大的兴趣，所述睫状上皮（CE）在哺乳动物眼睛的睫状体内发现，所述睫状上皮是类似于低等脊椎动物CMZ的区域。这些细胞表现出许多干细胞样的特性，尽管目前还不清楚这些细胞是否可以继续形成视网膜的所有细胞类型。更重要的是，这些细胞只有在培养皿中培养时才会增殖-它们在眼睛本身中处于休眠状态。这就提出了一个问题，即这些细胞是否代表了一群干细胞，它们与青蛙和鱼类中发现的干细胞相似，但在进化过程中失去了增殖和修复的能力。此外，可以想象，这些细胞可以被重新激活以产生新的视网膜神经元。调节低等脊椎动物中干细胞增殖和哺乳动物中干细胞样群体明显休眠的机制知之甚少。最近，一种被称为嘌呤能信号传导的信号传导途径被证明是开启眼睛形成所需的许多基因所必需的。我们还表明，这种信号传导机制对于控制胚胎中眼睛发育早期阶段视网膜祖细胞的增殖非常重要。在这里，我们的目的是确定是否嘌呤信号代表一个基本的调节机制，控制视网膜干细胞在睫状缘的增殖。此外，我们希望确定这个信号系统是否在进化过程中丢失或受到限制，从而为哺乳动物CE的干细胞不再增殖提供解释。我们已经发现嘌呤能信号参与了培养皿中哺乳动物视网膜干细胞的增殖。我们还发现，在哺乳动物CE中不存在对脑中其他部位嘌呤能介导的增殖至关重要的特定类型的受体，但当它们在培养皿中培养时，在这些细胞中发现了这种受体。这意味着有可能诱导哺乳动物眼睛中正常休眠的干细胞增殖并在眼睛中形成新的视网膜神经元。因此，我们的目标是首先检查嘌呤能信号在控制视网膜干细胞增殖的作用，在成年人的眼睛和培养皿。我们还将确定导致这种增殖的嘌呤能信号传导的下游途径。我们将比较进化上不同的物种，以检查这些动物的视网膜中的嘌呤信号的作用，最后我们将确定是否有可能重新激活的哺乳动物CE的干细胞的嘌呤信号。虽然目前只是理论上的，但最后一个目标可能为修复因疾病或损伤而受损的视网膜提供信息。