Scientists have resolved the mechanism controlling the maintenance of the light detectors - the cone photoreceptor outer segments - in the retina. With this knowledge, they have been able to induce the formation of functional photoreceptors in cultured retinas derived from embryonic stem cells. This opens up exciting new avenues for the study and treatment of blindness.
In about a third of all cases, loss of vision is caused by a loss of photoreceptor function. The most prevalent disease of this type - age-related macular degeneration (AMD) - is affecting a growing population of older adults. Others, such as retinitis pigmentosa or Stargardt disease, affect fewer but younger patients.
In recent years, therapeutic approaches using stem cells for retinal diseases such as AMD have gained a lot of attention. However, progress has been hampered by a lack of understanding of the molecular processes controlling the maintenance of cone photoreceptor outer segments - which serve as light detectors - and the inability to grow retinas with functional photoreceptors from stem cells.
Scientists led by Botond Roska (FMI Group leader) and Witold Filipowicz (FMI emeritus Group leader) have now successfully identified two small RNA molecules - both only approximately 20 nucleotides in length - necessary for the dynamic maintenance of the outer segments of cone photoreceptors in mice. In the absence of these microRNAs (miR-182 and miR-183), cone outer segments and cone vision is lost. Cone cells, one of the two types of photoreceptors present in the retina, are responsible for color vision and fine detail. The microRNAs thus control the maintenance of the retinal structures which are essential for the majority of our visual tasks. This research, reported in Neuron, started more than 5 years ago and was driven by Volker Busskamp and Jacek Krol - co-first authors of the paper - who are both postdoctoral fellows at FMI.
Most excitingly, miR-182 and miR-183 induced the formation of photoreceptor outer segments in cultured retinas derived from embryonic stem cells, generating responses to light.
Roska comments: "The understanding of the mechanisms leading to the formation and maintenance of outer segments - and thus functional photoreceptors - is highly valuable, as we can now derive functional retinas from stem cells under clearly defined conditions. The next step is to study the processes leading to the loss of outer segments in retinas derived from patients’ skin cells, and to find compounds that have an effect on these processes."
Stem cells in retinal diseases
Scientists have tried to obtain functional retinas by culturing induced pluripotent stem cells (iPSCs). These cells have been generated by forcing fully differentiated adult cells to express a set of stem cell transcription factors. Thus reprogrammed and dedifferentiated, they exhibit pluripotent qualities and can differentiate into a wide variety of cell types, including retinal cells. Prior to the Neuron publication, the molecules and mechanisms controlling the process of differentiation into a functioning photoreceptor were largely unknown.
iPSC-based cellular therapies hold promise in many areas of regenerative medicine.
Original publications
Busskamp V, Krol J, Nelidova D, Daum J, Szikra T, Tsuda B, Juettner F, Farrow K, Gross Scherf B, Patino Alvarez CP, Genoud C, Sothilingam V, Tanimoto N, Stadler M, Seeliger M, Stoffel M, Filipowicz W, Roska B (2014) MiRNAs 182 and 183 are necessary to maintain adult cone photoreceptor outer segments and visual function. Neuron
On Botond Roska and Witold Filipowicz
Botond Roska is interested in how neurons interact in local neuronal networks to compute behaviorally relevant functions. He studies these processes in the mammalian retina because it is well defined easily accessible and can be manipulated experimentally. He has also done research into retinitis pigmentosa, a rare disease that leads to blindness. In the course of these experiments he has been able to identify a novel approach to treat the disease.
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Witold Filipowicz is a pioneer in RNA research. He has studied this molecule long before the recent excitement around RNA interference (RNAi), microRNAs (miRNAs), and RNA’s newly defined role in gene regulation arose. His results, synergizing with others in the field, not only paved the way for a new view of the function of RNA in the cell, but laid the groundwork for harnessing RNA-driven processes for biomedical purposes. In the last couple of years, in particular, his characterization of human Dicer, the protein catalyzing the first step in RNAi, and his work on the function and metabolism of miRNAs, have demonstrated that small RNA molecules play a key role in gene regulation.
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