Researchers unlock regenerative potential of cells in the mouse retina

August 28, 2017
Regenerating Muller glia (yellow) in the mouse retina. Credit: Tom Reh

Cells within an injured mouse eye can be coaxed into regenerating neurons and those new neurons appear to integrate themselves into the eye's circuitry, new research shows. The findings potentially open the door to new treatments for eye trauma and retinal disease. The study appears in the July 26 issue of Nature, and was funded in part by the National Eye Institute (NEI), part of the National Institutes of Health.

"The findings are significant because they suggest the feasibility of a novel approach for encouraging regeneration in the mammalian retina, the light sensitive tissue at the back of the eye that dies in many blinding diseases," said Tom Greenwell, Ph.D., program director at NEI. "Importantly, the investigation also demonstrates that newly generated in the mouse retina not only look and behave like neurons, they also wire correctly to the existing neural circuitry at the back of the eye."

The study's lead investigator, Tom Reh, Ph.D., and his team at the UW Medicine in Seattle, looked to the zebrafish for clues about how to encourage regeneration in the mouse eye. When a zebrafish injures its eye, cells within the eye naturally regenerate, allowing the fish to maintain vision. Mammals lack this regenerative ability.

In studying zebrafish the research team homed in on Müller glia, a type of that supports the health and functioning of neighboring neurons, and that also exhibits an innate regenerative ability. Sometimes referred to as the stem cells of the zebrafish eye, Müller glia are the cells from which all other types of retinal cells are regenerated in the fish.

Earlier research from Reh's lab showed that in newborn mice, Müller glia can be directed to become by activating a transcription factor called Ascl1, which in turn activates a suite of genes involved in regeneration. By the time the mice reach adulthood, however, regions of the that are targeted by Ascl1 and that are required for regeneration become inaccessible. In other words, in adult mice, regions of the genetic code that are critical for regeneration are closed for business.

Nikolas Jorstad and Matt Wilken, graduate students in Reh's lab, screened a library of small molecules to find one that could reopen access to the genetic code in the adult mouse.

"We found that the commonly used anti-cancer agent trichostatin A (TSA) made critical regions of DNA accessible again. Ascl1 could then bind to those regions, which stimulated the regeneration of neurons in the adult mice," Jorstad said.

The researchers used an adult mouse model genetically engineered to express Ascl1 in Müller glia in response to tamoxifen, a commonly used breast cancer drug. In this engineered mouse, the green fluorescent protein (GFP) gene is inserted next to Ascl1, so that all cells expressing Ascl1 are labeled fluorescent green. Tamoxifen turns on Ascl1, and GFP tracks the cells where Ascl1 is expressed.

The researchers injured the mice retinas with a toxin that causes cell death in and interneurons, another type of retinal cell whose job it is to transmit signals from photoreceptors to the brain. They then injected the mice with TSA and tamoxifen. Over the next several weeks, the shape and behavior of the fluorescent green-labeled cells were observed to see if there was evidence of regeneration.

Proteins expressed by the observed cells were similar to those of interneurons. Analyses of genome structure further shored up evidence that the cells that were once Müller glia had been genetically reprogrammed and were now showing characteristics of interneurons.

Next, teaming up with electrophysiologists William Grimes, Ph.D. and Fred Rieke, Ph.D. of UW Medicine (Grimes has since moved to the University of Maryland, College Park), they looked at the cells' electrophysiological activity in the presence of light, taking advantage of the fact that Müller glia respond to light in a distinct, measurable pattern. About two weeks following injury, the cells responded to light as if they were interneurons.

"We're showing for the first time that Müller glia in the adult mouse can give rise to new neurons after injury, and these neurons have the gene expression pattern, the morphology, the electrophysiology, and the epigenetic program to look like interneurons instead of glia," Reh said.

The studied cells had formed functioning synapses - connections from one neuron to another - and responded to light in a way that's typical of a type of interneuron. The cells had also integrated with retinal cells that convey signals to the brain.

"These findings suggest that the regenerated cells were making synapses and integrating into both sides of the circuitry, presynaptically and postsynaptically," Reh said.

Reh envisions this approach could be useful for treatment of acute eye injuries and central retinal arterial occlusion - a stroke of the eye. The next step is to boost Müller glia numbers.

"Retinal injuries and blinding diseases of the retina tend to cause a massive loss of neurons. We need a way to stimulate the regeneration of Müller glia, in addition to strategies for coaxing them to differentiate into other types of ," Reh explained.

Strategies are also needed to regenerate photoreceptors and ganglion cells, still other types of retinal cells that are lost in degenerative eye diseases such as glaucoma and macular degeneration. Reh's lab is investigating other types of regenerative strategies to address all the retinal cell types.

Explore further: Scientists regenerate retinal cells in mice

More information: Nikolas L. Jorstad et al, Stimulation of functional neuronal regeneration from Müller glia in adult mice, Nature (2017). DOI: 10.1038/nature23283

Related Stories

Scientists regenerate retinal cells in mice

July 26, 2017
Scientists have successfully regenerated cells in the retina of adult mice at the University of Washington School of Medicine in Seattle.

Study helps explain how zebrafish recover from blinding injuries

March 9, 2017
Researchers at Vanderbilt University in Nashville, Tennessee have discovered that in zebrafish, decreased levels of the neurotransmitter gamma-aminobutyric acid (GABA) cue the retina, the light-sensing tissue in the back ...

New insight into eye diseases

September 28, 2016
Many diseases that lead to blindness, such as glaucoma and macular degeneration, are caused by the death of certain cells in the human retina that lack the ability to regenerate. But in species such as zebrafish these cells, ...

Immune system found to control eye tissue renewal in zebrafish

July 17, 2017
Researchers at Johns Hopkins Medicine report evidence that zebrafishes' natural ability to regenerate their eyes' retinal tissue can be accelerated by controlling the fishes' immune systems. Because evolution likely conserved ...

Reprogramming 'support cells' into neurons could repair injured adult brains

November 20, 2014
The portion of the adult brain responsible for complex thought, known as the cerebral cortex, lacks the ability to replace neurons that die as a result of Alzheimer's disease, stroke, and other devastating diseases. A study ...

Recommended for you

Coming soon: Glaucoma self-care, from home?

September 23, 2017
(HealthDay)—For many glaucoma patients, repeat trips to a doctor's office to check on their eyes can be a real pain.

Researchers identify potential biomarkers of age-related macular degeneration

September 12, 2017
Patients with any stage of age-related macular degeneration (AMD) carry signs of the disease in their blood that may be found through special laboratory tests, according to a new study led by AMD researchers based at Massachusetts ...

Researchers unlock regenerative potential of cells in the mouse retina

August 28, 2017
Cells within an injured mouse eye can be coaxed into regenerating neurons and those new neurons appear to integrate themselves into the eye's circuitry, new research shows. The findings potentially open the door to new treatments ...

Antioxidant supplement cost saving and effective for degenerative eye disease

August 24, 2017
A supplement that combines antioxidants with zinc and copper is a relatively inexpensive and effective means of halting the progression of a certain type of degenerative eye disease, concludes research published online in ...

Researchers identify key compounds to resolve abnormal vascular growth in AMD

August 21, 2017
A compound of specific bioactive products from a major family of enzymes reduced the severity of age-related macular degeneration (AMD) in a preclinical model, according to a new study led by Massachusetts Eye and Ear researchers. ...

World's blind population to soar: study

August 3, 2017
The world's blind will increase threefold from about 36 million today to 115 million in 2050 as populations expand and individuals grow ever older, researchers said Thursday.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.