The Genomic Basis of Human Induced Pluripotent Stem (iPS) Cell Differentiation into Eye-Like Tissues.

构成我们身体的细胞具有特定的功能，并适应它们所在的特定组织。例如，皮肤细胞不同于眼睛细胞，而眼睛细胞不同于血细胞。当然，每种细胞类型都有其独特的作用。成熟细胞，无论它们在哪个组织中，都被称为分化细胞，因为它们已经根据自己在帮助形成的组织中的生物学作用而定制。很长一段时间以来，人们普遍认为，一旦一个细胞“选择了自己的道路”并分化成一种特定类型的细胞，它就走上了一个不可逆转的过程。但是，在2012年，两位科学家(约翰·格登爵士(英国剑桥大学)和Shinya Yamanaka教授(日本京都大学))因他们的研究而获得诺贝尔奖，他们的研究表明，分化的成体细胞可以从基因上重新编程为分化较少的细胞，能够形成许多不同类型的细胞。这种细胞被称为诱导多能干细胞，通常缩写为iPS细胞。我们新计划的研究源于我们在日本大阪大学的长期合作伙伴西田光二教授和林龙平教授与附近京都大学的山中教授合作所做的一项发现。他们的工作表明，人类iPS细胞可以在实验室中生长形成一个圆盘，其中不同区域的细胞与眼睛不同部位的细胞相似，如晶状体、视网膜和角膜。这一发现令人兴奋，因为它将使科学家能够进行复杂的实验，以更好地了解人眼的发育。从人类iPS细胞中获得的类眼睛细胞在未来也有潜力用于治疗各种眼病的新疗法。令人兴奋的是，大阪团队展示了iPS来源的细胞，这种细胞与眼睛的外表面最相似，被称为角膜上皮，能够在角膜失明模型中恢复视力。因此，我们可以在实验室从人类iPS细胞中培养出类眼组织，但我们需要全面了解是什么遗传过程驱动了这一过程，因为目前这些过程尚不清楚。我们将进行研究，利用我们的合作者西田教授和Hayashi教授发现的方法，确定可以从人类iPS细胞产生的类眼细胞类型(如角膜、晶状体或视网膜)的完整体系。这将代表着一项重大的新合作，将使用最新技术来了解人类iPS细胞生长和分化为眼状组织的遗传驱动因素。我们还将使用人类iPS细胞来研究一种重要的基因，称为TCF4，它在世界上最常见的角膜致盲疾病富氏内皮角膜营养不良症中受损。重要的是，这些新的信息将帮助我们了解健康的角膜内皮细胞的功能机制以及当它们发生故障时会发生什么，这些知识将为未来基于人类iPS细胞的新型疗法的研究奠定基础。总体而言，与我们在日本的同事的合作将使我们在人眼发育、角膜细胞生物学和支撑人类iPS细胞分化的遗传基础方面的知识取得重大进展。

The cells that comprise our body have specific functions and are adapted to suit the particular tissue in which they exist. Skin cells, for example, are different to eye cells, which are different to blood cells. And, of course, each cell type has its own distinctive role. Mature cells, whichever tissue they are in, are called differentiated cells because they have become tailored to their biological role in the tissue they help form. For a long time, it was accepted that once a cell had "chosen its path" and differentiated into a particular type of cell, it had embarked on an irreversible process. But, in 2012 two scientists were awarded the Nobel Prize (Professor Sir John Gurdon (Cambridge University, UK) and Professor Shinya Yamanaka (Kyoto University, Japan)) for their research, which showed that differentiated adult cells could be genetically reprogrammed to a less differentiated cell, capable of forming many different cell types. Such cells are called induced pluripotent stem cells, commonly abbreviated to iPS cells.Our new planned research originates from a discovery made by our long-term collaborators in Osaka University, Japan, Professors Kohji Nishida and Ryuhei Hayashi, working with Professor Yamanaka in nearby Kyoto University. Their work showed that human iPS cells can grow in the laboratory to form a disc in which cells in different areas resemble cells found in different parts of the eye, such as the lens, retina and cornea. This discovery is exciting because it will allow scientists to conduct sophisticated experiments to better understand human eye development. The eye-like cells obtained from the human iPS cells also have the potential, in the future, to be used in new treatments for a large variety of eye disorders. Excitingly, the Osaka team showed that iPS-derived cells that most closely resemble the outer surface of the eye known as the corneal epithelium, were able to restore vision in a model of corneal blindness. So, eye-like tissues can be grown in the laboratory from human iPS cells, but we need to comprehensively understand what genetic processes drive this because currently these are unknown.We will conduct research to determine the complete repertoire of eye-like cell types (e,g. cornea, lens or retina) that can be produced from human iPS cells using the methods discovered by our collaborators, Professors Nishida and Hayashi. This will represent a major new collaboration that will use the latest technologies to understand the genetic drivers of human iPS cell growth and differentiation into eye-like tissues. We will also use the human iPS cells to study an important gene, called TCF4, which is damaged in the most common corneal blinding disease in the world, called Fuchs' endothelial corneal dystrophy. Crucially, the new information will help us understand the mechanisms by which healthy corneal endothelial cells function and what happens when they malfunction, knowledge that will lay the ground for future studies of novel human iPS cell-based therapies. Overall, this collaboration with our colleagues in Japan will lead to significant advances in our knowledge of human eye development, corneal cell biology and the genetic basis that underpins human iPS cell differentiation.