'Cell extrusion' could be responsible for vision loss

Visual cells in the human retina may not simply die in some diseases, but are in fact mechanically transported out of the retina beforehand. That’s according to scientists from the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), the Helmholtz Centre for Environmental Research (UFZ) and the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden, who published their findings in the journal Nature Communications.

It is estimated that a quarter of people over the age of 60 suffer from age-related macular degeneration (AMD). The macula is a special region within the human retina that is needed, among other things, for high-resolution colour vision. In AMD, thousands of light-sensitive visual cells, the so-called photoreceptor cells, are lost in the macula.

“This was the starting point for our research project: we observed that photoreceptors are lost, but we could not detect any cell death in the retina,” said Professor Mike Karl, a researcher at DZNE and CRTD. “Half of all photoreceptors disappeared from the retinal organoid within 10 days, but obviously they did not die in the retina. That made us curious.”

Searching for the cause of this disappearance, the research team came across a study from 2012 whereby Jody Rosenblatt from King’s College London described the extrusion of living cells — the mechanical ejection of cells from epithelia. The thereby extruded cells then only die in succession. Rosenblatt demonstrated this mechanism in simple epithelial cells of the kidney, but Karl and his team have now shown that this extrusion can also be triggered in the much more complex retina, consisting of several different cell types, and leads to neurodegeneration. Interestingly, this cell extrusion could explain the outlying cells that have been previously reported in the aging and diseased retina of patients with AMD and other diseases, but have not been studied in detail until now.

The researchers worked with retinal organoids — organ-like, three-dimensional models of the human retina grown from human stem cells in the laboratory. These organoids provide some characteristics of the human macula. The team found that two substances previously described in various neurodegenerative diseases — the proteins HBEGF and TNF — are sufficient to trigger degeneration in the retinal organoid. During this process, the researchers filmed the organoids in real time through live imaging, considered the gold standard for cell tracking.

“We were able to capture the degeneration of photoreceptors through cell extrusion in the lab,” Karl said. The scientists found that this extrusion is triggered by activation of the protein PIEZO1, a sensor for biomechanical forces. That biomechanics may play a larger role in retinal degeneration is a new finding.

“The retina is not known to be a biomechanically active tissue such as a muscle,” Karl said. “It was known that diseases of the nervous system are associated with changes in the shape of cells, but to which extent biomechanical regulators are involved has not yet been studied in detail.”

Thanks to the organoids, he and his team were able to observe these processes in an accelerated manner: while it takes several years or even decades for photoreceptors to disappear in patients, such a process could now be reproduced in the laboratory in just 40 days. The researchers now want to find out whether this mechanism occurs in human patients in the same way as in organoids.

The researchers also found that pharmacological agents could prevent extrusion in an experimental setting in their model. They used a special snake venom to block the mechanosensor PIEZO1 on the cells. As a result, not only were the photoreceptors not ejected, but further pathological changes in the retina were prevented.

“This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD,” Karl said.

Image caption: Microscopic images of lab-grown mini retinas, so-called human retina organoids. The left image shows a section of a healthy (control) organoid, whereas the right image shows an organoid section with pathological changes. On the right, there is a massive loss of photoreceptor neurons that are labelled in green. The red colour shows the pathological Müller glia cells that are not present in the healthy control. Image ©Völkner et al, Nature Communications, 2022.

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