The Dresden scientists developed a robust method to produce high numbers of human photoreceptor cells and used them to restore daylight perception in mice with degenerated eyesight.
Photoreceptor cell transplantation is a promising intervention that in the future may help recover vision in people with blinding diseases. A team of researchers led by Professor Marius Ader of the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden has just reported another preclinical breakthrough in a new study published in the Journal of Clinical Investigations. The team developed a robust method to produce high numbers of human photoreceptor cells. The researchers show that such human photoreceptors can incorporate en masse into the retinas of partially degenerated mice. The incorporated photoreceptors developed characteristics of normal photoreceptors and could detect daylight in mice with impaired sight.
The new study represents a step forward in an effort to bring photoreceptor transplants to patients with blinding diseases. “To our knowledge, this is the first time that someone has achieved such a massive integration of transplanted photoreceptors into the retina,” says Professor Marius Ader, research group leader at the Dresden Center for Regenerative Therapies (CRTD) at the Technical University of Dresden, which led the study.
Several factors at play
To massively increase the number of incorporated photoreceptors, scientists optimized several critical factors. They established that the age of the transplanted photoreceptors is decisive. “We managed to find what appears to be a perfect step to transfer the photoreceptors into the retina. If we do it with younger or older photoreceptors, we see a big drop in the rate of incorporation,” says Professor Ader.
The team also found that integration into the retina requires more time. “We saw that photoreceptor cells need a considerable time, up to six months, to establish interactions and build an appropriate network with the remaining cells in the mouse retina,” says Professor Ader.
The interaction with the remaining, intact cells of the mouse retina was found to be a key factor. “About 30% of the cells in the retina are other cells that support the work of photoreceptors. In our case, we clearly saw that the interaction of the transplanted cells with the host retinal cells was crucial for successful incorporation and maturation. Some of these remaining cells provided scaffolding for the new photoreceptors and helped them organize themselves properly,” adds Professor Ader.
Robust and unlimited source of photoreceptors
To produce photoreceptors, the team used stem cells to grow mini-retinas in a lab dish, according to a protocol developed by their collaborator Professor Mike Karl. Once the mini-retinas had grown to a necessary stage, Dr. Sylvia Gasparini and Karen Tessmer, scientists from Prof. Ader’s team who performed most of the experiments in this study, harvested the photoreceptors for transplantation.
“Obtaining a pure population of photoreceptors is yet another challenge. To remedy this, our collaborator Prof. Volker Busskamp has developed a new stem cell line in which conical photoreceptor cells have special labels. These tags do not interfere with their function but allow us to robustly sort out the photoreceptors from the rest of the cells in the mini-retinas. explains Professor Ader.
These induced pluripotent stem cell lines provide a virtually unlimited source of photoreceptors and can potentially be used in future clinical applications.
Restore the perception of daylight
In this study, the team focused on mice with partially degenerated retinas that lacked only one of two types of photoreceptors. “The mice only had damaged cones, which are responsible for daytime vision, a situation similar to several blinding diseases in human patients,” says Professor Ader. The approach was different from previous studies because the remaining cells of the retina were not damaged. Until now, most transplantation attempts have targeted models of blinding diseases at a very advanced stage, characterized by degeneration of all photoreceptors.
Together with their collaborators from the Institute of Natural and Medical Sciences in Tübingen, the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE) in Dresden, the DRESDEN-concept Genome Center and facilities for electron and optical microscopy from the Center for Molecular and Cellular Bioengineering (CMCB) at TU Dresden, the team used a variety of techniques to thoroughly validate the maturation and function of the transplanted photoreceptors. They were able to demonstrate that the new photoreceptors not only adopt the physiological characteristics of normal photoreceptors but also, as shown by their collaborator Professor Günther Zeck, function correctly by supplying signals to nerve cells downstream of the retina.
A new paradigm?
“We were excited to see how well human photoreceptors incorporated through cell support in the host mouse retina. It might be useful to rethink future transplantation approaches. Perhaps intervention at some point, when the patient’s retina is still able to meaningfully interact with the grafted photoreceptor, could also yield a beneficial outcome in humans,” Prof. Ader concludes.
Reference: Gasparini SJ, Tessmer K, Reh M, et al. Transplanted human cones integrate into the retina and function in a model of murine cone degeneration. J Clin Invest. 2022;132(12). do I:10.1172/JCI154619
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