Elderly man's eyes
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Researchers at the University of Maryland School of Medicine (UMSOM) have for the first time identified stem cells in the region of the optic nerve, which transmits signals from the eye to the brain. Their findings point to a new notion about why the most common form of glaucoma may develop, and point to potential new ways to treat a leading cause of blindness in adults in the United States.

“We believe these cells, called neural progenitor cells, are present in the optic nerve tissue at birth and remain for decades, helping to nourish the nerve fibers that form the optic nerve,” said study lead Steven Bernstein, MD, PhD, professor and vice chair of the department of ophthalmology and visual sciences at UMSOM. “Without these cells, the fibers may lose their resistance to stress, and begin to deteriorate, causing damage to the optic nerve, which may ultimately lead to glaucoma.” The researchers reported their findings in the Proceedings of the National Academy of Sciences (PNAS), in a paper titled, “The optic nerve lamina region is a neural progenitor cell niche.”

Glaucoma affects more than three million people in the United States, causing blindness in about 120,000. The disorder results from damage to the optic nerve, which is usually linked with increased pressure in the eye due to a build-up of fluid that does not drain properly. Blind spots can develop in a patient’s visual field, which gradually widen over time.

In both humans and mice the optic nerve (ON) that connects the eye and the brain grows about 80% postnatally, Bernstein and colleagues explained. Through their studies, the researchers examined a narrow band of tissue known as the optic nerve lamina region (ONLR). Less than 1 mm wide, the lamina lies between the light-sensitive retina tissue at the back of the eye and the optic nerve. The long nerve cell fibers extend from the retina through the lamina, into the optic nerve. The lamina is also the primary damage site in the age-related form of glaucoma, open angle glaucoma (OAG).

“The ONLR has a number of unusual characteristics: it inhibits intraocular myelination, enables postnatal ON myelination of growing axons, modulates the fluid pressure differences between eye and brain, and is the primary lesion site in the age-related disease open angle glaucoma (OAG),” the investigators wrote.

The results of their studies indicated that these lamina progenitor cells may be responsible for insulating the nerve fibers immediately after they leave the eye, supporting the connections between nerve cells on the pathway to the brain.

“This is the first time that neural progenitor cells have been discovered in the optic nerve,” said Bernstein. “Without these cells, the nerve is unable to repair itself from damage caused by glaucoma or other conditions. This may lead to permanent vision loss and disability. The presence of neural stem/progenitor cells opens the door to new treatments to repair damage to the optic nerve, which is very exciting news.”

The studies indicated that stem cells in the lamina niche bathe the neuron extensions with growth factors, as well as aiding in the formation of the insulating myelin sheath. “It took 52 trials to successfully grow the lamina progenitor cells in a culture,” said Bernstein, “so this was a challenging process.” The researchers were able to confirm the presence of these stem cells through the use of antibodies and genetically modified animals to identify the specific protein markers on neuronal stem cells. Through their experiments the team also needed to identify the correct mix of growth factors and other cell culture conditions that would be most conducive for the stem cells to grow and replicate.

The investigators were able to show that these neural progenitor cells (NPCs) could be coaxed into differentiating into several different types of neural cells, including both neurons and glial cells, which are known to be important for cell repair and cell replacement in different brain regions. “These NPCs generate both forms of macroglia: astrocytes and oligodendrocytes, and can form neurospheres in culture,” they noted. “Using reporter mice with SOX2-driven, inducible gene expression, we show that ONLR-NPCs generate macroglial cells for the anterior ON.”

The discoveries may have major implications for the development of new treatments for eye diseases that affect the optic nerve, and in particular age-related disorders, such as open angle glaucoma. “Both mouse and human ONLR-NPC numbers decline during aging,” the scientists stated. “The loss of ONLR-NPCs in humans may alter the balance between degeneration and repair, contributing to the emergence of age-related ON diseases, such as OAG, a progressive ONLR-associated neuropathy.” Aging is linked with progressive resistance to glaucoma treatment, the researchers further pointed out. ONLR-NPC depletion may thus contribute to OAG progression because there are fewer supporting glial cells and neurotrophic factors produced to promote nerve cell survival under stress.

“We hypothesize that ONLR-NPCs present in younger individuals may be protective, and the age-related loss of ONLR-NPCs may contribute to disease progression via the inability to repair stress-related damage … Understanding the roles of ONLR-NPCs may enable new therapeutic strategies to treat ON disease.”

Bernstein and his research team plan to use genetically modified mice to see how depletion of lamina progenitor cells contributes to diseases such as glaucoma, and prevents repair. Future research will be needed to explore neural progenitors repair mechanisms. “If we can identify the critical growth factors that these cells secrete, they may be potentially useful as a cocktail to slow the progression of glaucoma and other age-related vision disorders,” Bernstein added.

“This exciting discovery could usher in a sea change in the field of age-related diseases that cause vision loss,” said E. Albert Reece, MD, PhD, executive vice president for medical affairs, University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers distinguished professor and dean, UMSOM. “New treatment options are desperately needed for the millions of patients whose vision is severely impacted by glaucoma, and I think this research will provide new hope for them.”

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