Researchers at UCL Great Ormond Street Institute of Child Health (UCL GOS ICH) have grown ‘mini eyes’ to assess blindness. The breakthrough study, published in Stem Cell Reports, described how 3D retinal organoids were grown and analysed to study a genetic eye condition called Usher Syndrome.
I spy with my ‘mini eye’
Eyes have a highly ordered and intricate structure. The light-sensing cells (rod cells) are arranged in the image-processing region in the back of the eye (the retina). This means that it can be challenging to imitate the same structure to study vision loss. This is especially true for Usher Syndrome, which is the most common genetic cause of combined deafness and blindness. Previous research used animal cells to study the syndrome, but the same type of vision loss could not be replicated.
Researchers at UCL GOS ICH were able to grow ‘mini eyes’ called retinal organoids. Rod cells self-organised into layers that resembled how they are organised in the retina. The various layers, cell types and subcellular features of the human retina were effectively grown in the lab and were comparable to the control organoids.
Dr Yeh Chwan Leong, first author and Research Associate at UCL GOS ICH said, “It’s difficult to study the inaccessible tiny nerve cells of the patient’s retina as they are so intricately connected and delicately positioned at the back of the eye. By using a small biopsy of skin, we now have the technology to reprogramme the cells into stem cells and then create lab-grown retina with the same DNA, and therefore same genetic conditions, as our patients.”
An eye-opening experimental approach
The same type of vision loss seen in Usher syndrome was accurately recreated by the researchers. First, skin samples from patients were reprogrammed to generate pluripotent stem cells. The stem cells were then used to grow 3D organoids (figure 1). At 21 weeks the organoids had multiple cell layers, which were identified using immunohistochemistry. By 35 weeks, the stem cells had differentiated just like the control stem cells, creating retinal organoids that resembled the real human retina.
The stem cells developed into a 3D retina, where the rod cells carried the genetic mutation of interest. The researchers were then able to investigate the underlying genetic aetiology of Usher syndrome. RNA sequencing was used to study the rod cells. By comparing the transcriptomes of control and patient-derived organoids, differential gene expression was observed. Bulk RNA sequencing revealed abnormal gene expression in patient-derived cells. Single-cell RNA sequencing highlighted dysregulated metabolic pathways in the cells.
Keep an eye out for future applications
The researchers studied rod cells at an individual level and in greater depth than ever before by using the ‘mini eyes’ and RNA sequencing analysis. The ‘mini eye’ models are likely to have considerable implications for future research and development of treatments. Using the same protocol, models of other genetic eye conditions could be developed. Organoids could also be used to design and test treatments, including gene editing therapies.
Professor Jane Sowden, senior author and Professor of Developmental Biology and Genetics at UCL said, “We are very grateful to patients and families who donate these samples to research so that, together, we can further our understanding of genetic eye conditions, like Usher syndrome. Although a while off, we hope that these models can help us to one day develop treatments that could save the sight of children and young people with Usher syndrome.”
