Nanoscale Structural Characterisations of Ocular Tissues Derived from Human iPS Cells

人类 iPS 细胞来源的眼组织的纳米级结构表征

• 批准号: BB/X000966/1
• 负责人: Andrew Quantock
• 金额: $ 90.95万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000966%2F1
• 关键词: Nanoscale; Structural; Characterisations; Ocular; Tissues

The cells that comprise our body have specific functions and are adapted to suit the particular tissue in which they exist. Mature cells are generally known as differentiated cells because they have become tailored to their biological role. 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 journey. However, in 2012 Professors Sir John Gurdon and Shinya Yamanaka, of Cambridge and Kyoto Universities, respectively, were awarded the Nobel Prize for their research, which showed that differentiated adult cells could be genetically reprogrammed to become less differentiated and capable of forming many different cell types. Such cells are called induced pluripotent stem cells, commonly abbreviated to iPS cells. The new research we propose originates with the discovery, made with our collaborators in Japan, that human iPS cells (hiPSCs) can be cultivated in the laboratory to grow in a manner that mimics the way cells in the human eye develop before birth.Component tissues of the eye have interrelated developmental pathways, with the corneal and conjunctival epithelia that cover the eye's surface, the lens within the eye and the tear-producing lacrimal gland all evolving from the same cell type. Thin flat sheets of corneal and conjunctival epithelia have been generated from hiPSCs, and some of the corneal sheets have been used to restore sight in patients with vision loss. New research is now starting to show how hiPSCs can be used to form 3D organoids (miniaturised versions of an organ or selected aspects of it) of lacrimal gland and lens. These are key ocular tissues, which, respectively, help synthesise the tear film and focus light onto the retina. How accurately these organoids mimic the natural tissue, however, is yet to be fully appreciated. We now plan a series of experiments using high-specification electron microscopes and high-intensity x-ray beams (including use of the world's most powerful experimental x-ray source, the SPring8 synchrotron in Japan) to obtain a comprehensive understanding of 3D organoids of lacrimal glands and lenses generated from hiPSCs.Vision loss has a devastating impact on an individual's life. The societal cost, too, is severe, with researchers at The London School of Economics estimating that the economic cost to the UK of sight loss stands at £25.2 billion each year, predicted to rise to £33.5 billion by 2050. Healthy lacrimal glands and lenses are essential for correct vision. Dysfunctional lacrimal glands cause severe dry eye syndrome, which affects tens of millions of people worldwide and can result in corneal ulceration and blindness if left untreated. Cataracts (cloudy lenses), moreover, are the single major reason for sight loss, especially in the elderly. Our research has the potential to have real future impact because well-characterised 3D lacrimal gland-like and lens-like organoids formed from cells of a human origin represent an excellent resource, as an alternative to experiments on animals, for scientists to devise and test new medications to treat/prevent sight-threatening diseases of the lacrimal gland and lens. In addition, the hiPSC-derived organoids, when more fully understood and further investigated, have the potential to be used in transplant surgery. In the near/mid-term future, research into organoid transplantation will likely be directed towards the treatment of lacrimal gland, rather than lens, pathology because of the availability of implantable synthetic lenses. The immediate value of properly characterised hiPSC-derived lens-like organoids is predicted to lie in their use to investigate medications to inhibit or reverse lens protein aggregation and the development of cataract in old age.

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。成熟细胞通常被称为分化细胞，因为它们已经根据自己的生物学角色进行了调整。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，它就踏上了一段不可逆转的旅程。然而，2012年，剑桥大学和京都大学的约翰·格登爵士和山中伸弥教授分别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通过基因重组变得不那么分化，并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。我们提出的这项新研究源于与我们在日本的合作者的一项发现，即可以在实验室培养人类iPS细胞(HiPSCs)，以模仿人眼细胞在出生前发育的方式。眼睛的组成组织有相互关联的发育路径，覆盖眼睛表面的角膜和结膜上皮、眼睛内的晶状体和产生泪液的泪腺都是从同一种细胞类型进化而来的。HiPSCs已经产生了薄薄的扁平的角膜和结膜上皮细胞，其中一些角膜薄膜已经用于恢复视力丧失的患者的视力。一项新的研究现在开始表明，HiPSCs可以用来形成泪腺和晶状体的3D有机体(器官或其选定方面的微型版本)。这些都是关键的眼组织，它们分别帮助合成泪膜和将光线聚焦到视网膜上。然而，这些有机化合物对自然组织的模拟有多准确，还有待充分认识。我们现在计划进行一系列实验，使用高规格的电子显微镜和高强度的X射线束(包括使用世界上最强大的实验X射线源，日本的SPring8同步加速器)，以全面了解由HiPSC产生的泪腺和晶状体的3D器官。视力损失对个人的生活有毁灭性的影响。社会成本也很严重，伦敦政治经济学院的研究人员估计，英国每年因失明而造成的经济损失为252亿英镑，预计到2050年将上升到335亿英镑。健康的泪腺和晶状体对于矫正视力是必不可少的。泪腺功能障碍会导致严重的干眼综合征，这种综合症影响着全球数千万人，如果不治疗，可能会导致角膜溃疡和失明。此外，白内障(混浊的晶状体)是导致失明的唯一主要原因，尤其是在老年人中。我们的研究有可能对未来产生真正的影响，因为由人类起源的细胞形成的具有良好特征的3D泪腺样和晶状体样器是科学家设计和测试新药来治疗/预防泪腺和晶状体疾病的极好资源，作为动物实验的替代方案。此外，当更充分地了解和进一步研究时，HiPSC衍生的有机类化合物有可能用于移植手术。在近期/中期内，由于可植入人工晶状体的出现，器官移植的研究可能会集中在泪腺的治疗上，而不是晶状体的病理上。据预测，经过适当表征的HiPSC衍生的晶状体类有机化合物的直接价值在于，它们被用于研究抑制或逆转晶状体蛋白聚集和老年白内障发展的药物。