Discovery opens possibilities for understanding glaucoma and new therapeutic strategies
July 31, 2020
NEI
Microscopy image in blue and green showing mouse optic nerve

Mouse optic nerve, showing progenitors becoming myelinating cells.

A National Eye Institute-funded study has identified a type of stem cell called a neural progenitor cell, in a region of the optic nerve, which connects the eye to the brain. The optic nerve becomes damaged in open-angle glaucoma, a leading cause of visual impairment in the U.S. Future studies of these neural progenitor cells may help explain how glaucoma develops and may lead to new therapies to treat it. The report on animal and human findings appears online July 28, 2020 in the Proceedings of the National Academy of Sciences of the United States of America.

“Prior to our study, the optic nerve was not known to have stem cells, suggesting a limited ability of this tissue to repair itself,” said primary investigator Steven Bernstein, M.D., Ph.D., professor of Ophthalmology and research chief, Lab of Molecular Research in the Department of Ophthalmology and Visual Sciences at the University of Maryland School of Medicine, Baltimore.

“As it turns out, neural progenitor cells are in human optic nerve tissue at birth and they stick around for decades, helping to keep the axons that form the optic nerve healthy,” he said.

The researchers homed in on a narrow band of tissue called the optic nerve lamina. No more than 1 mm long, the lamina straddles the light-sensitive retina at the back of the eye and the optic nerve that extends to the brain to produce vision. The lamina is a transition zone, through which the axons of neurons called retinal ganglion cells pass. The axons extend from the eye and bind together to form the optic nerve. Axons emerging from the eye are unmyelinated, meaning that they lack the myelin sheath that surrounds nerve axons and acts as a kind of wire insulation. The axons become myelinated after passing through the optic nerve lamina.

Using a technique that images cells and structures in living tissue, researchers discovered that the optic nerve lamina of both humans and rodents contained a vascularized niche structure that’s unique to the region where stem cells form. The niche lacks specific proteins that form a typical blood-brain barrier, allowing communication with surrounding tissue, and offering a nurturing environment for stem cells. Antibody and gene expression studies evaluating specific protein markers of neural progenitor cells confirmed their presence.

“It took 52 trials to grow the optic nerve lamina region neural progenitor cells in culture,” said Bernstein, adding that these “stem cells are like New Yorkers. They need crowded places to thrive and relax.” At last the team identified a mix of growth factors and other culture conditions conducive for neural progenitor cells to grow and replicate. These progenitor cells eventually differentiated into several neural cell types, including glial cells, which are known to be important for cell repair and cell replacement in different brain regions.

When cultured, the optic nerve lamina region-isolated cells also formed smooth-walled globes called neurospheres, structures unique to neural progenitor stem cells.

Studies using genetically modified (transgenic) mice enabled the researchers to selectively localize the neural progenitor cell activity.  By tagging gene expression, the scientists were able to identify cell type as the cells divided and matured. Transgenic mice that were designed to lose neural progenitor cells developed optic nerve abnormalities, including the thinning of the myelin sheath that normally covers the optic nerve axons after passing through the lamina.

Studies of human optic nerve tissue from donors ages 7 months to 71 years indicated that the population of optic nerve lamina region neural progenitor cells declines as people age. “When you look at a 9-year-old or a 20-year-old, they have huge numbers of these cells, and then they start to go away. By age 70, there’s none,” Bernstein said. The discovery that humans have an age-depletable niche of optic nerve lamina stem cells could help explain why people become more vulnerable to glaucoma as they age, and why over time they often stop responding to standard glaucoma therapies that involve lowering intraocular pressure.

In follow-up investigations, Bernstein plans to use transgenic mice to see if depleting the neural progenitor cells at early ages contributes to glaucoma severity. He also plans to study the role of neural progenitor cells in repairing damage to the optic nerve.

“In glaucomatous disease, do you first have disease resistance because of the progenitor cells, and as these cells are used up, do you get an acceleration of the disease process? If we could identify the cocktail of growth factors that these cells secrete, could that potentially be used to enable retinal ganglion cells to increase their resistance to glaucoma and to stress as one ages?” he added.

 

The work was supported by NEI grant R01EY015304, and by a National Institutes of Health shared instrument grant 1S10RR26870-1.

For more information about glaucoma, visit https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/glaucoma

References:

Bernstein, SL; Guo, Y; Kerr, C;  Fawcett, RJ; Stern, JH; Temple, S; Mehrabian, Z. “The optic nerve lamina region is a neural progenitor cell niche.” Jul 28, 2020.  Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2001858117

 

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