The start of the field of stem cell biology dates back to 1938, when Hans Spemann suggested that a differentiated nucleus can express pluripotency. This was followed by decades of research leading to the Nobel Prize being awarded to Professor Sir Martin J. Evans, Professor Sir John B. Gurdon and Professor Shinya Yamanaka based on their work. This created a new area of research and progress has moved rapidly. We are now at a stage when we can grow mini organs (organoids) in a lab.
Animal models have contributed tremendously to our understanding of disease mechanisms; however, they do not always provide a solid platform for accurate recapitulation of the human system. Several key differences exist between animal models and humans including life span and physiology. In addition, for some developmental and pathological processes no animal models currently exist. This is especially significant for the disorders affecting the retina.
A pioneering study published by Yoshiki Sasai’s group in 2012 showed that human embryonic stem cells are capable of self-organising into three-dimensional (3D) optic cups or retinal organoids. Numerous studies followed describing similar findings using human induced pluripotent stem cells (iPSCs). Remarkably, retinal organoids grown in a lab contain laminated retinal cell layers and can show functional response to light, which opens tremendous opportunities to study prenatal human eye development and disease modelling using near-physiological structures.
Retinal organoids are also becoming a powerful tool in the process of drug discovery, as recently shown by researchers at Newcells Biotech and Newcastle University in a study led by Professor Majlinda Lako published in the Stem Cells journal (doi: 10.1002/stem.2883). The addition of a known retinotoxin to the 3D organoids showed similar response to what is seen in vivo in retinas of adult mice, the finding that demonstrated the applicability of the in vitro 3D retina in toxicology studies.
3D retina derived from patient iPSCs has been shown to be a useful tool in elucidating disease mechanisms, including studies of Retinitis Pigmentosa (RP). RP is one of the most common inherited forms of retinal degeneration and affects more than 1 million people worldwide. It is characterised by progressive visual loss leading to night blindness and visual field constriction eventually leading to the loss of central vision. Management of RP remains challenging with no effective treatments currently available. Photoreceptors, in particular rods at the early stages of the disease, and retinal pigment epithelium (RPE) are the most affected cells in RP.
IPSC-derived 3D optic cups provide an unprecedented tool to study the mechanism of RP using a physiologically-relevant model, which is especially useful in modelling genetically heterogeneous diseases such as RP. Last year, researchers at the University of Edinburgh used retinal organoids to gain mechanistic insight into the development of an X-linked form of RP caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene, which gives instructions for making the RPGR protein localised in photoreceptor connecting cilium (doi: 10.1038/s41467-017-00111-8).
Interestingly, mutations in ubiquitously expressed genes can also give rise to retina-specific phenotype seen in RP patients. One of such genes is pre-mRNA processing factor 31 (PRPF31) involved in catalysing pre-mRNA splicing. Animal models do no recapitulate the RP phenotype caused by PRPF mutations in humans.
Professor Majlinda Lako and a team of collaborators, including Professor Reinhard Lührmann, Dr Sushma-Nagaraja Grellscheid and Professor Colin Johnson, used iPSC-derived retinal organoids and RPE to shed light on the mechanism of retinal degeneration seen in patients with PRPF31 gene mutation. The researchers were able to provide molecular characterisation of RP clinical phenotype.