Scientists discover new potential mechanism for vision loss

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Visual cells in the human retina are mechanically transported out of the retina beforehand rather than simply dying in some diseases. Scientists at the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and the Center for Regenerative Therapy (CRTD) at the Technical University of Dresden have discovered this. For their research, they used miniature human retinas made in the laboratory, so-called organoids. In a new issue of the journal Nature Communications, they report on their findings. age-related macular degeneration (AMD).

This principle, known as cell extrusion, has not yet been studied in neurodegenerative diseases. “

Research Group Leader, Prof. Mike Carl

AMD is the leading cause of blindness and severe visual impairment in Germany. It is estimated that one in four people over the age of 60 suffer from AMD. The macula is a special area within the human retina that is especially needed for high-resolution color vision. In AMD, thousands of light-sensitive visual cells, so-called photoreceptors, are lost in the macula.

“This was the starting point for our research project. We observed a loss of photoreceptors, but we could not detect retinal cell death,” said the researchers at DZNE’s Dresden site and TU’s CRTD. explains Mike Karl, who is doing Dresden. “Half of all photoreceptors disappeared from the retinal organoid within his 10 days, but apparently they did not die in the retina. That piqued our curiosity.”

An in-depth investigation into the cause has been initiated for investigators involving DZNE and CRTD, and the Helmholtz Center for Environmental Research (UFZ). This led them to his 2012 study (doi:10.1038/nature10999): Jody Rosenblatt of his College of Kings, London describes the extrusion of living cells, i.e. the mechanical This is the first time I’ve written about Extrusion. The cells extruded by it only die continuously. She demonstrated this mechanism in simple kidney epithelial cells. In a pioneering study, Mike Carl and his team showed that this extrusion can also be triggered in the much more complex retina, which consists of several different cell types, leading to neurodegeneration. This cell extrusion could explain the previously reported dislodging cells in aging and diseased retinas of patients with AMD and other diseases, but has not been studied in detail until now.

The researchers took advantage of previously developed techniques. We used so-called retinal organoids. This is his three-dimensional model that resembles a human retinal organ grown from human stem cells in the laboratory. These organoids provide several features of the human macula. The team found that two of his substances—the proteins HBEGF and TNF—previously reported in various neurodegenerative diseases, were sufficient to cause degeneration of retinal organoids.

During this process, the researchers filmed the organoids in real time by so-called live imaging, which is considered the gold standard for cell tracking. “By extruding cells in the lab, we were able to capture photoreceptor degeneration,” says Mike Karl. Scientists found that this extrusion is caused by the activation of the protein PIEZO1, a biomechanical force sensor.

It is a new finding that biomechanics may play a greater role in retinal degeneration. “The retina is not known to be a biomechanically active tissue like muscle. The extent to which mechanical regulators are involved has not yet been studied,” says Karl. Thanks to the organoids, he and his team were able to observe the process in an accelerated way, so to speak: just 40 days. In a next step, researchers now want to examine whether this mechanism occurs in human patients in the same way it does in organoids. Initial findings suggest that this may be the same mechanism. suggests, but evidence is still lacking.

In their study, the Dresden researchers also found that pharmacological agents could prevent extrusion in the experimental setting of their model. blocked. As a result, not only were photoreceptors not ejected, but further pathological changes in the retina were prevented. “This gives hope for the future development of preventive and therapeutic strategies for complex neurodegenerative diseases such as AMD,” he sums up Mike Karl.


Journal reference:

Faulkner, M. and others. (2022) HBEGF-TNF induces complex outer retinal pathology with extrusion of photoreceptor cells in human organoids. Nature Communications.

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