| Abstract |
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 fully adapted to their biological role. For a long time, it was thought 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 discovering that differentiated adult cells could be genetically reprogrammed to become less differentiated and thus 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 (1). Based on this hiPSC technology, we now have exciting opportunities to probe the unique genetic, chemical and cellular changes that occur in hiPSCs as they recapture the processes of human eye development. Crucially, for the first time we will correlate the genetic status of hiPSCs with their chemical identity. This will be achieved via a combination of state-of-the-art spatial transcriptomics to reveal the genetic mechanisms behind the formation of hiPSC-derived eye-like structures, aligned to X-ray microscopy and infrared spectroscopy experiments at the UK’s National Synchrotron Radiation Facility, Diamond Light Source, near Oxford, to establish the spatiotemporal chemical patterning within the eye-like structures at nm-resolution. In achieving this, transcriptomic status can be linked to the types of biologically important elements that a cell expresses. The synchrotron-based analysis will be augmented with immunoelectron microscopy to identify key biological components of developing hiPSCs via antibodies tagged with nano-gold particles. Parallel studies of developing human eyes will allow us to closely monitor how the emerging hiPSC constructs mimic actual human eye development. Our work aligns closely with BBSRC’s Strategic Delivery Plan in terms of “helping realise the transformative potential of engineering biology” and attaining “a deeper understanding of biological systems”. Indeed, we have shown how hiPSCs can be cultured to form functional eye-related tissues, such as tear-producing lacrimal glands (2). Also, many diseases of the eye are age-related, and our research will be aligned to BBSRC’s desire to “address the challenges of increasing healthy life expectancy”. With this in mind, it has recently become evident that hiPSC-derived corneal epithelial cell sheets are able to recover the sight of patients with severely impaired vision, including individuals in their 60s and 70s (3). The future application of the hiPSC technology described here has the real potential to be transformative, attaining a deeper understanding of the combined genetic, chemical and cellular underpinnings of how hiPSCs replicate whole eye development. Hayashi … Quantock, Tsujikawa, Nishida. Co-ordinated ocular development from human iPS cells and recovery of corneal function. Nature 2016;531:376-380. doi:10.1038/nature17000 Hayashi … Quantock, Nishida. Generation of 3D lacrimal gland organoids from human pluripotent stem cells. Nature 2022;605:126-131. doi:10.1038/s41586-022-04613-4 Soma … Quantock, Hayashi, Nishida. iPS cell-derived corneal epithelium for transplant surgery: A single-arm, open-label, first-in-human interventional study in Japan. Lancet 2024;404:1929-1939. doi:10.1016/S0140-6736(24)01764-1 |
