In the human body, no cell works alone. They constantly communicate and work alongside one another to maintain balance and respond to threats like injuries, stress and diseases.
Scientists at the Indiana University School of Medicine are taking a deeper look into how three types of cells found in the eye’s retina interact when grown together using human stem cells in a dish. Their findings, recently published in the journal PNAS, revealed that inflammation from two of the cells can harm the third cell type — neurons connecting the eye to the brain. This damage is commonly associated with glaucoma and other types of optic nerve disorders.
The research team, led by Jason Meyer, PhD, the A. Donald Merritt Professor of Medical and Molecular Genetics, and Jade Harkin, PhD, first author of the study and a PhD graduate of the IU School of Medicine, built the platform, which models retinal ganglion cells that connect the eye to the brain as well as the two supporting cells, astrocytes and microglia.
“What we found is that microglia, the brain’s immune cells, play a double role, in which they help retinal ganglion cells grow, mature and become more electrically active in healthy states,” Meyer said, “but when we primed the microglia into an inflammatory state, they turned harmful and began to damage those same neurons. Astrocytes then joined in, amplifying the damage.”
Close to 3 million Americans have glaucoma, and it’s the second-leading cause of blindness worldwide, according to the U.S. Centers for Disease Control and Prevention. The neurodegenerative disorder damages the optic nerve, formed by retinal ganglion cells. Once those cells are gone, vision loss is permanent.
Meyer said growing evidence indicates that the fate of retinal ganglion cells in glaucoma depends heavily on the health of microglia and astrocytes. Microglia are immune cells that can either nurture neurons or turn against them, he said, and astrocytes are support cells that maintain brain health and support neurons but can also shift into an inflamed state.
The researchers used a triculture platform to grow all three cell types together using human pluripotent stem cells, which can be developed into any type of cell in the body.
“Our model shows, in human cells, that inflammation from these support cells can be a driver of that damage, giving future studies a clearer target,” Meyer said, who leads the stem cell research group at Stark Neurosciences Research Institute. “We were struck by how much the inflamed microglia and astrocytes worked together to harm the retinal ganglion cells. The combination was more damaging than either cell type or even what we would have predicted as the sum of the two supporting cell types.”
Meyer said the model has the potential serve as a testing ground to screen potential drugs that reduce inflammation or protect the neurons in retinal and optic nerve diseases and even also neurodegenerative conditions within the brain such as Alzheimer’s or Parkinson’s diseases.
“What excites us is that this is a fully human model, with all three cell types made from the same genetic starting point. That means we can ask questions about human disease directly,” Meyer said. “Our work points to inflammation as another piece of the puzzle and gives scientists a human system to search for therapies that protect retinal ganglion cells.”
His team will next work to make the model even more realistic by moving toward three-dimensional culture systems, like retinal organoids and microfluidic "organ-on-a-chip" platforms, so it more closely mirrors how these cells are arranged in the retina and optic nerve. His lab previously developed an “optic nerve of a chip” to study how glaucoma damages separate regions of retinal ganglion cells.
The research was supported by funding from the National Eye Institute, the Gilbert Family Foundation and the BrightFocus Foundation.
