Four to 12 percent of people undergoing cataract surgery to replace a cloudy lens with a clear artificial one develop posterior capsule opacification (PCO). Also referred to as secondary cataract, PCO is the most common vision-compromising complication of cataract surgery. In a new study, scientists find that the growth factor TGF-beta may play a role in the formation of secondary cataract, suggesting a direction for research into strategies to prevent it. The study appears in Molecular Biology of the Cell and was funded by the National Eye Institute, part of the National Institutes of Health.
“Cataract surgery is the most common ocular surgery performed. Preventing posterior capsule opacification would spare thousands of people from needing laser capsulotomy, a procedure with potential risks that costs the U.S. more than $150 million annually,” said Houmam Araj, Ph.D., lens and cataract program director at NEI. “In addition to shedding light on how secondary cataracts form, these findings present some exciting insights into the growth factor TGF-beta that have implications far beyond the eye,” he said.
During cataract surgery, a hole is made in the front of the lens capsule, the outer layer that surrounds the lens. A surgeon inserts an ultrasonic probe that emulsifies the lens, which is then drawn out through the hole. A new, artificial lens is then placed in the lens capsule. Cataract surgery typically improves vision with long-lasting results. However, some patients develop secondary cataract in the following weeks and months. This happens when residual lens epithelial cells left behind from the old, emulsified lens accumulate at the back of the lens capsule and transform into one of two types of cells that cause problems: lens fiber cells and myofibroblasts. Lens fiber cells become bloated with proteins called crystallins, which causes them to scatter light as it passes through the lens. Myofibroblasts generate large amounts of molecules outside the cell, creating a matrix that causes the lens capsule to wrinkle, which obstructs vision.
To better understand the factors that cause residual lens epithelial cells to differentiate into these two distinct cell types, the study’s lead investigator, Linda S. Musil, Ph.D., of Oregon Health & Science University, Portland, and her team cultured purified embryonic chick lens cells to determine the effects of various growth factors on cell differentiation. Previous studies suggest that the growth factor TGF-beta becomes highly active in response to surgery-induced injury. “Though it occurs on a small scale, cataract surgery creates a huge wound response,” she said, referring to the cascade of molecularly-driven processes that orchestrate tissue repair and prevent infections following an injury. Previous studies have shown that when active TGF-beta is overexpressed in the intact lens, myofibroblasts form. By contrast, little is known about the factors that promote the formation of lens fiber cells.
Musil’s team found that adding active TGF-beta to their culture system induced the lens epithelial cells to differentiate into either myofibroblasts or lens fiber cells, while adding a TGF-beta inhibitor reduced differentiation. Other growth factors failed to induce similar cell differentiation. Both cell types were found in the same cultures, often right next to each other, as has been reported in people with secondary cataract. In addition, the presence of TGF-beta was associated with the migration of lens cells, a requirement for accumulation at the back of the lens capsule and secondary cataract.
Next, they assessed whether TGF-beta had a direct effect on lens epithelial cell differentiation, or if it was indirectly enabled by molecular signaling downstream of TGF-beta activation. Using their lens culture system, they found that blocking the downstream p38 kinase pathway with an inhibitor, prevented myofibroblast formation. Similarly, inhibiting the MTOR pathway prevented the formation of lens fiber cells.
Musil said that future studies are needed to assess the contribution of other factors on cell fate. One possibility is cell density. Looking at the distribution of cell types within the culture, lens fiber cells tend to congregate in densely packed multilayered islands while myofibroblasts form a single layer fringe surrounding those islands.
From a basic science perspective, the findings shed new light on TGF-beta. In cancer, TGF-beta is known to first suppress and then later promote tumor growth as disease progresses, a phenomenon known as the TGF-beta paradox. This latest study suggests that TGF-beta plays yet another dual role in a very different type of disorder. “Our studies show that TGF-beta is capable of concurrently directing two disparate cell fates in non-transformed lens epithelial cells,” Musil said.
In the interest of finding a treatment to prevent secondary cataract, the team used their lens culture system to test drugs for their ability to block PCO. They found that the multikinase inhibitor rebastinib, a drug that is currently in phase I clinical trials for cancer, prevented TGF-beta from inducing cell migration as well as the formation of myofibroblasts in both chick lens cells and in rat lens explants. Work is in progress to find agents that inhibit both myofibroblast and lens fiber cell formation. Such agents may be included in artificial lenses to prevent the formation of secondary cataract, Musil said.
The study was supported by grants from NEI (R01EY022113 to Linda Musil and R01EY017146 to Judith West-Mays).
Boswell BA, Korol A, West-Mays JA, Musil LS. Dual function of TGF-beta in lens epithelial cell fate: implications for secondary cataract. Mol Biol Cell. Feb 16 2017. doi:10.1091/mbc.E16-12-0865.
NEI leads the federal government’s research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.
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