Ganglion cells created in mice in an attempt to repair diseased eyes

Abstract: Researchers have induced non-neural cells that mimic ganglion cells in the eyes of mice, effectively reducing the impact of certain eye diseases. They hope to next replicate their technique on humans to help restore vision lost 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 induced to mimic specific ganglion cells in the eyes of mice.

It is hoped that one day this advance could create a new way to treat a range of neurodegenerative diseases, including glaucoma, macular degeneration and Parkinson’s disease.

A UW Medicine team led by Tom Reh, a professor of biological structure at the University of Washington School of Medicine, previously showed that neurons can be coaxed from glial cells in the retinal tissue of mice. Now they have improved the process to produce specific cells.

“We could make primarily just one type of neuron — a bipolar neuron,” Reh said. “And as we would say at the time, ‘We can make one type of neuron that no one loses to disease.’

“So while it was pretty amazing, it also wasn’t super clinically relevant. Since then, we’ve been trying to figure out if we can tinker with this process further in mammals and see if we can expand that repertoire of types of neurons that can regenerate.”

A paper describing the results appeared on November 23 in Scientific progress. Postdoctoral researcher Levi Todd and graduate student Wesley Jenkins in Reh’s lab co-authored the paper.

Over the past three years, researchers have been studying 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 the structure and function of the cell.

Previously, the team learned how to use transcription factors to revert glia to a more primitive state known as a progenitor cell. Further treatment can then push the progenitor cell in other directions.

In this case, they tried to create retinal ganglion cells — the type lost to glaucoma.

This approach “could potentially have very broad applicability because the principle is that you start the ball rolling by turning your glia into a progenitor-like cell, but now you don’t let that cell do whatever it wants to do,” Reh said. “You control it and direct it along certain developmental paths. I think it will be generally applicable in other areas of brain and spine repair.”

Todd said the researchers are building a “book” of transcription factors.

“Usually when you have a disease like Parkinson’s, the dopamine neurons die,” he said. “If you have glaucoma, the ganglion cells die. We want to find out how to convert glia into that specific type of neuron.”

The team plans to study whether the same process will work in the eye tissue of humans and monkeys. Reh said the work is ongoing and other teams are also conducting similar research.

“I hope that in three years we will show that it works in monkeys and humans,” Reh said.

“I think we are the pioneers of this approach in the field, and others are coming now. It won’t surprise me if we aren’t the first to find a magic mix for cones or a magic mix for some particular subtype of ganglion cell. But I think we’ve set a paradigm for how you can improve on this and how you can now get better at it and improve on it.”

Computational biologist Connor Finkbeiner, postdoctoral fellow Marcus J. Hooper, undergraduate researcher Phoebe C. Donaldson, postdoctoral fellows Marina Pavlou, Juliette Wohlschlegel, and Norianne Ingram, and Fred Rieke, professor of physiology and biophysics, also participated in the research.

About this visual neuroscience research news

Author: Press office
Source: University of Washington
Contact: Press Office – University of Washington
Picture: Image credit to Levi Todd

Original research: Open access.
“Reprogramming Müller glia to regenerate ganglion-like cells in the adult mouse retina with developmental transcription factors” Levi Todd et al. Scientific progress

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Abstract

Reprogramming Müller glia to regenerate ganglion-like cells in the adult mouse retina with developmental transcription factors

Many neurodegenerative diseases cause degeneration of specific types of neurons. For example, glaucoma leads to the death of retinal ganglion cells, leaving other neurons intact. Neurons do not regenerate in the central nervous system of adult mammals.

However, in non-mammalian vertebrates, glia cells spontaneously reprogram into neural 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 glia.

Here, we test additional transcription factors (TFs) for their ability to direct regeneration to specific types of retinal neurons. We engineered mice to express different combinations of TFs in Müller glia, including Ascl1, Pou4f2, Islet1, and Atoh1.

Using immunohistochemistry, single-cell RNA sequencing, a single-cell transposase-accessible chromatin sequencing assay, and electrophysiology, we found that retinal ganglion cells can regenerate in the damaged adult mouse retina in vivo with targeted overexpression of developmental retinal ganglion cell TFs.