New potential mechanism for vision loss discovered

In some diseases, photoreceptors in the human retina may not simply die, but are first mechanically removed from the tissue. This has now been discovered by scientists from the German Centre for Neurodegenerative Diseases (DZNE) and the Centre for Regenerative Therapies Dresden (CRTD) at TU Dresden. For their research, they used human mini-networks produced in the laboratory, so-called organoids. In the latest issue of the journal Nature Communications, they report on their discovery, which paves the way for entirely new research approaches, particularly in connection with age-related macular degeneration (AMD).

„This principle, known as cell extrusion, has not yet been investigated in neurodegenerative diseases,

says Prof Dr Mike Karl, who heads the research group. AMD is the main cause of blindness and severe visual impairment in Germany. According to estimates, a quarter of people over the age of 60 suffer from AMD. The macula is a special region of the human retina that is needed for sharp colour vision, among other things. In AMD, thousands of light-sensitive visual cells, known as photoreceptors, die in the macula. 
„This was the starting point for our research project: we observed that photoreceptors are lost, but could not detect any cell death in the retina“, explains Mike Karl, who works at the Dresden site of the DZNE and at the CRTD. Half of all photoreceptors disappeared from the retinal organoid within ten days, but they obviously did not die in the retina. This made us curious.“

In addition to the DZNE and the CRTD at the TU Dresden, the researchers also involved the Environmental Research Centre Leipzig (UFZ) – began an extensive search for the causes. This led them to a study from 2012 (doi: 10.1038/nature10999): Jody Rosenblatt from King’s College in London was the first to describe the extrusion of living cells – the mechanical ejection of cells from a tissue. The cells that are then ejected die as a result. She demonstrated this mechanism in simple epithelial cells of the kidney. Mike Karl and his team have now shown in their pioneering work that this extrusion can also be triggered in the much more complex retina, consisting of several different cell types, and leads to degeneration. Researchers had previously discovered that some cells in AMD patients were located outside the retina. However, the cause of this was previously unknown. Cell extrusion could now provide the long-missing explanation.

The scientists utilised a technique that they had previously developed: They are working with so-called retinal organoids - an organ-like, three-dimensional model of the human retina that is grown from human stem cells in the laboratory. These organoids have some specific characteristics of the human macula. The team found that two substances previously described in various neurodegenerative diseases - the proteins HBEGF and TNF - were sufficient to induce degeneration in the retinal organoid.

During this process, the researchers filmed the organoids in real time; so-called live imaging is considered the gold standard for tracking changes in cells. „We were able to record the degeneration of photoreceptors through cell extrusion in the lab“, says Mike Karl. The scientists found that this extrusion is triggered by activation of the protein PIEZO1, a sensor for biomechanical forces.

The fact that biomechanics may play a greater role in retinal degeneration is a new finding. „The retina is not known to be a biomechanically active tissue like a muscle. It was known that diseases in the nervous system are associated with changes in the shape of cells, but the extent to which they are regulated by biomechanical forces has not yet been investigated," says Karl. Thanks to the organoids, he and his team were able to observe the processes to a certain extent in fast motion: While it takes several years or even decades for photoreceptors to disappear in AMD patients, this process could now be traced in the laboratory in just 40 days. In the next step, the researchers now want to find out whether this mechanism occurs in the patient's retina in the same way as in the organoids. Initial data and many similarities in content suggest that it could be the same mechanism, but proof is still pending.

In their study, the Dresden researchers also found that extrusion can be prevented under laboratory conditions in the model when experimental substances are used: They used a special snake venom to block the PIEZO1 mechanosensor on the cells. As a result, not only were the photoreceptors not ejected, but further pathological changes in the retina were also prevented. This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD," summarises Mike Karl.

&about the German Centre for Neurodegenerative Diseases (DZNE)
The DZNE is a research institute funded by the federal and state governments and has ten sites across Germany. It is dedicated to diseases of the brain and nervous system such as Alzheimer's, Parkinson's and ALS, which are associated with dementia, movement disorders and other serious health impairments. To date, there is no cure for these diseases, which place an enormous burden on countless sufferers, their families and the healthcare system. The aim of the DZNE is to develop new strategies for prevention, diagnosis, care and treatment and to put them into practice. To this end, the DZNE co-operates with universities, university hospitals and other institutions in Germany and abroad. The institute is a member of the Helmholtz Association and is one of the German Centres for Health Research. www.dzne.de

&about the Centre for Regenerative Therapies Dresden (CRTD)
At the Centre for Regenerative Therapies Dresden (CRTD) at TU Dresden, top researchers from more than 30 countries are working on new therapeutic approaches. They are deciphering the principles of cell and tissue regeneration and exploring their use for the diagnosis, treatment and cure of diseases. The CRTD links laboratory and clinic, links science and clinic, uses expertise in stem cell research, developmental and regenerative biology to ultimately achieve a cure for diseases such as Alzheimer's and Parkinson's, haematological diseases such as leukaemia, metabolic diseases such as diabetes as well as eye and bone diseases.
The CRTD was founded in 2006 as a research centre of the German Research Foundation (DFG) and was funded as a DFG Research Centre and Cluster of Excellence until 2018. Since 2019, the CRTD has been funded by TU Dresden and the Free State of Saxony.
The CRTD is one of three institutes of the central scientific institution Centre for Molecular and Cellular Bioengineering (CMCB) at TU Dresden.

Source: Press release Technische Universität Dresden. In: idw from 01.12.2022