Summary: The researchers induced non-neural cells that mimic ganglion cells in the eyes of mice, effectively reducing the impact of certain eye diseases. They then hope to replicate their technique in humans to help restore vision lost due to eye disease.
Source: University of Washington
While fish, reptiles and even some birds can regenerate damaged brain, eye and spinal cord cells, mammals cannot. For the first time, non-neuronal cells have been made to mimic specific ganglion cells in mouse eyes.
The hope is that one day this breakthrough could create a new avenue for treating various neurodegenerative diseases, including glaucoma, macular degeneration and Parkinson’s disease.
A UW medicine team led by Tom Reh, professor of biological structure at the University of Washington School of Medicine, had previously shown that neurons could be coaxed from glial cells in mouse retinal tissue. Now they have refined the process to produce specific cells.
“We could only make one type of neuron, the bipolar neuron,” Reh said. “And as we said at the time, ‘We can make the one kind of neuron that nobody loses to disease.’
“So while it was pretty amazing, it wasn’t very clinically relevant either. Since that time, we’ve been trying to figure out if we can tinker with this process more in mammals and see if we can expand this repertoire of neuron types that can be regenerated.
An article describing the results appeared on November 23 in Scientists progress. Postdoctoral researcher Levi Todd and graduate student Wesley Jenkins from Reh’s lab are co-lead authors on the paper.
Over the past three years, researchers have studied proteins called transcription factors in vertebrates, such as zebrafish, that have regenerative abilities. Transcription factors are proteins that bind to DNA and regulate gene activity. This, in turn, controls the production of proteins that determine a cell’s structure and function.
Previously, the team learned how to use transcription factors to revert glia to a more primitive state known as a progenitor cell. Further processing can then nudge the progenitor cell in other directions.
In this case, they tried to create retinal ganglion cells, the type lost in glaucoma.
This approach “could potentially have very broad applicability because the principle is that you get the ball rolling by turning your glia into a progenitor-like cell, but now you’re not letting that cell do whatever it wants,” Reh said. . “You control it and channel it into specific developmental trajectories. I think it’s going to be generally applicable in other areas of brain repair and spine repair.
Todd said researchers are creating a “playbook” of transcription factors.
“Usually when you have a disease like Parkinson’s disease, dopamine neurons die,” he said. “If you have glaucoma, the ganglion cells die. We want to understand how to turn glia into this specific type of neuron. »
The team plans to study whether the same process will work in human and monkey eye tissue. Reh said work is ongoing and other teams are also pursuing similar research.
“Hopefully we can show in three years that it works in monkeys and humans,” Reh said.
“I think we are pioneering this approach in the field, and more are coming now. It won’t surprise me if we’re not the first to find the magic mix for cones or the magic mix for a particular ganglion cell subtype. But I think we’ve set the paradigm of how you can move forward and how you can now improve and refine it.
Computational biologist Connor Finkbeiner, postdoctoral fellow Marcus J. Hooper, undergraduate researcher Phoebe C. Donaldson, postdoctoral researchers Marina Pavlou, Juliette Wohlschlegel and Norianne Ingram, and Fred Rieke, professor of physiology and biophysics, also participated. looking.
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About this visual neuroscience research news
Author: Press office
Source: University of Washington
Contact: Press Office – University of Washington
Image: Image is credited to Levi Todd
Original research: Free access.
“Reprogramming Müller’s glia to regenerate ganglion-like cells in the retina of adult mice with developmental transcription factors” by Levi Todd et al. Scientists progress
Summary
Reprogramming Müller’s glia to regenerate ganglion-like cells in the retina of adult mice with developmental transcription factors
Many neurodegenerative diseases cause the degeneration of specific types of neurons. For example, glaucoma causes retinal ganglion cells to die, leaving other neurons intact. Neurons are not regenerated in the central nervous system of adult mammals.
However, in non-mammalian vertebrates, glial cells spontaneously reprogram into neuronal progenitors and replace neurons after injury.
We have recently developed strategies to stimulate the regeneration of functional neurons in the retina of adult mice by overexpressing the proneural factor Ascl1 in Müller’s glia.
Here we test additional transcription factors (TFs) for their ability to direct regeneration to particular types of retinal neurons. We engineered mice to express different combinations of TFs in Müller’s glia, including Ascl1, Pou4f2, Islet1, and Atoh1.
Using immunohistochemistry, single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin sequencing, and electrophysiology, we find that retinal ganglion-like cells can be regenerated in damaged adult mouse retina in vivo with targeted overexpression of developing retinal ganglion cells TF.
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