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，并适合适合其存在的特定组织。成熟的细胞通常被称为分化细胞，因为它们已根据其生物学作用量身定制。很长一段时间以来，人们就认为，一旦一个细胞“选择了路径”并区分了特定类型的单元，它就开始了不可逆转的旅程。然而，在2012年，剑桥和京都大学的约翰·古顿爵士和山内亚爵士分别因其研究而获得诺贝尔大学奖，这表明，差异化的成人细胞可以通常重新编程，从而变得较小的差异化并能够形成许多不同的细胞类型。这些细胞称为诱导多能干细胞，通常缩写为IPS细胞。 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 development 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从同一细胞类型演变。 hipscs产生了薄薄的角膜和结膜上皮的薄片，一些角膜片被用来恢复视力丧失的患者的视线。现在，新的研究开始表明如何使用HIPSC形成泪腺和镜头的3D器官（微型版本或其所选方面的微型版本）。这些是关键的眼组织，分别有助于合成泪膜并将光聚焦到视网膜上。然而，这些类器官模仿天然组织的准确程度尚未得到充分理解。 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.社会成本也很严重，伦敦经济学院的研究人员估计，到2050年到2050年，对英国视力损失的经济成本为252亿英镑，预计为335亿英镑。健康的酸性腺腺和镜头对于正确的视力至关重要。功能失调的泪腺会引起严重的干眼综合症，这会影响全球数千万人，如果未治疗，可能会导致角膜溃疡和失明。此外，白内障（多云的镜头）是视力丧失的唯一主要原因，尤其是在过去。我们的研究有可能产生真正的未来影响，因为由人类来源的细胞形成的特征良好的3D富集腺样和晶状体类器官代表了一种极好的资源，作为动物实验的一种替代方法，以供科学家设计和测试新药物以治疗/预防曲线腺腺体和Lens和Lens和Lens的视力危害。此外，当对hipsc衍生的类器官进行更充分的理解和进一步研究时，有可能用于移植手术。在近期/中期的未来，由于可植入的合成透镜的可用性，对类器官的研究可能会针对泪腺的治疗，而不是晶状体。预计正确特征的HIPSC衍生的透镜状类器官的直接价值在于它们用于研究抑制或反向晶状体蛋白聚集和老年白内障的药物的用途。