Researchers have found that old, fully mature cells in the cornea can become stem cells again. The cells rebuilt the eye’s stem cell supply even after every last stem cell had been destroyed.
Cells that had nearly stopped dividing pulled off the reversal and kept the tissue healthy for the rest of the animal’s life.
The cornea is the clear dome at the front of the eye, and losing its stem cells can rob a person of sight.
A repair system the body runs on its own raises the prospect that some blindness could one day be reversed without a transplant from a donor.
A cornea rebuilds itself
The cornea keeps itself clear thanks to a small, hidden workforce. Its own limbal stem cells sit in a narrow ring at the outer rim, called the limbus.
Their offspring travel inward to replace surface cells as they wear away.
A team led by Professor Ruby Shalom-Feuerstein, a stem cell biologist at the Technion-Israel Institute of Technology (Technion), set out to see what happens when that workforce is gone.
Working with mice, the researchers stripped away the entire ring of stem cells while leaving the surrounding tissue bed untouched. Through the clear cornea, they tracked the repair.
The cornea grew back. Tracing individual cells showed the new stem cells were not survivors that had escaped the scalpel but ordinary mature corneal cells that had reversed course.
Biologists call this dedifferentiation, a process in which a specialized cell reverts to a stem cell.
The transformation was remarkably complete.
Within about 40 days, the reverted cells were almost indistinguishable from the cornea’s native stem cells, sharing more than 99 percent of their gene activity. Ordinary corneal cells share only 85 to 90 percent.
They also behaved like the real thing, supplying fresh surface cells and keeping the cornea clear for 6 months.
That result ran against a long-held assumption. Losing a tissue’s stem cells was thought to be irreversible, ending in scarring and disease, which is why serious repair has usually meant transplanting cells from elsewhere.
“We were surprised to discover that the cornea can regenerate itself even after the destruction of all its stem cells,” said Shalom-Feuerstein.
The oldest cells made a comeback
Cells reversing into stem cells was not new. Earlier work had caught committed cells in fast-renewing tissues doing it.
One influential study showed differentiated cells in the airway becoming stable, working stem cells after the resident ones were removed.
What stayed unclear was the reach of that ability. In those tissues the cells that reverted were young, made only days earlier, so no one knew whether genuinely old cells held the same capacity.
The cornea gave the team a way to test it. Because a corneal cell’s distance from the rim tracks its age, the researchers could pick out the eye’s oldest cells.
These were mature cells sitting at the center that had spent about four months drifting inward and had all but retired from dividing. Even these old cells made a comeback.
When moved onto a stripped corneal rim, they switched their stem cell programs back on, rebuilt both the quiet reserve and the active working pool, and kept the cornea clear for nearly a year.
An immune cell trigger
Something had to tell those cells to change. The team traced the signal to macrophages, the immune cells that rush to any injury to clear debris and bacteria.
They flooded the stripped rim within a day or two, and cutting their numbers by about three-quarters left the stem cells largely unable to return.
The macrophages did more than clean up. As they gathered they released signaling molecules.
Two of them, a growth factor called IGF1 and an immune messenger called CCL2, did most of the work of nudging mature cells back toward a stem cell state.
Blocking the pair stalled the repair, and adding them back restored it.
The reversal has its limits
The reversal has firm limits. It only worked when the tissue bed that houses the stem cells came through the injury intact, and it stayed within the cornea’s own family of cells.
When cells from the conjunctiva, the membrane that covers the white of the eye, moved in to repopulate the cornea’s outer rim instead, they could not transform into corneal stem cells.
The surface clouded and filled with blood vessels – the signature of blindness caused by stem cell loss.
The eye is not alone. In the skin, researchers have found that the stem cells responsible for hair color can shift in and out of a stem cell state as their surroundings change.
The finding suggests this kind of cellular flexibility is a normal part of tissue maintenance, not just an emergency response to injury.
A path toward restoring vision
Whether human corneas can do the same is not yet settled. The experiments ran almost entirely in mice, and the team could not directly test reversal in human corneal cells.
Working with donated human tissue, they found the same macrophage molecules helped cultured human stem cells keep their identity – a sign the pathway may carry over.
The stakes are clearest for people who have lost the cornea’s stem cells to burns, infection, or disease. Their vision is already gone or fading.
The study shows that a mature cell, even a very old one, can revert to a fully functional stem cell and remain that way for life, provided the surrounding tissue and immune cells supply the right signals.
What remains unknown is how to trigger that process on demand and whether other organs possess the same hidden regenerative ability.
“The next challenge is learning how to control it and how to use it for regenerative medicine,” said Shalom-Feuerstein.
The study is published in the journal Nature Communications.
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