Cells Use Patch to Heal Rips and Tears, Avoid Destruction and Disease

Most cells in the body rapidly repair many tears to their delicate surface that result from everyday use, trauma or disease, says a Medical College of Georgia researcher.

Dr. Paul L. McNeil’s decade-old hypothesis says that when the cell surface is so compromised, calcium ions from outside the cell rush in, prompting membranes inside the cell to fuse and patch the hole.

The cell biologist seems to have proven his theory by taking the red blood cell — the one cell in the body known to lack these internal membranes — and documenting its inability to self-repair.

By contrast, his work, published in this week’s Proceedings of the National Academy of Sciences, documents the repair process in the simple sea urchin egg and fibroblasts as well as neurons.

Previous work in his lab has shown that skeletal muscle cells — which are constantly stretched and strained through normal use, never mind harsh stresses such as distance-running — are among the most frequently injured and rapidly repaired of the cells: within 30 seconds they are resealed. The pain and muscle tiredness that comes with exercise likely results from such tearing.

“Many of our cells could not survive in the mechanically harsh environment of our bodies if they could not repair,” he says. In fact when tearing becomes excessive due to structural defects in the skeletal muscle wall, disease results, such as the crippling Duchenne’s muscular dystrophy.

He hopes that by understanding the cellular and molecular details of this ongoing repair, he can one day help make it happen.

It’s no surprise to Dr. McNeil that red blood cells are injured and don’t survive. They constantly bang against blood vessel walls as they deliver oxygen throughout the body. And, it’s been known for years that these short-lived cells lack the internal membranes that subdivide most cells. The good news is that the bone marrow is constantly producing red blood cells so they don’t have to last long.

To document what happens to these and other cells when torn, Dr. McNeil developed a technique that uses a precise laser to puncture the cell membrane, then, with the help of a dye marker, illustrate the resulting activity. When the red blood cells are torn, calcium ions, found in excess outside of cells, rush in much like a crowd at an Augusta golf course. But rather than initiating a fix ? as they do in muscle cells, for example ? they just keep coming until their levels become deadly. Inside, they change the red blood cell’s surface property so it becomes recognizable to the liver, which consumes it, says Dr. McNeil, noting that the cells lose their hemoglobin and are useless at that juncture anyway.

By contrast in muscle cells, Dr. McNeil has found that these calcium ions, which are naturally present in higher levels outside of cells and in low concentration within, move inside the cell through the tear, prompting little vesicles — membranes that subdivide the cell — to fuse, forming a large internal membrane that fuses with the surface membrane at the site of the tear, effectively sealing it up in less than 30 seconds. In the minutes and hours following this acute repair, the cell will repair the resulting damage to its internal membranes.

“So the prediction of this patch hypothesis is a cell in our body which lacks internal membrane would not be able to repair rapidly,” he says. “What we found is that red blood cells cannot repair tears in their surfaces so they provide a test of this hypothesis. This is one way science proceeds,” he says of his efforts to challenge his own findings. “You make a hypothesis then, if you are really serious about it, you attempt to falsify it.”

With collaborators at the University of Iowa College of Medicine and the Howard Hughes Medical Institute, he’s also looking at specific components of repair, some of which may be implicated in specific diseases.

“For me this confirms a prediction that I would have made long ago: that if you can’t repair tears, because they are occurring all the time in your body, you are going to have disease,” Dr. McNeil says. “What this confirms is the biological importance of this repair process.”

His research is largely funded by the National Aeronautics Space Administration which has a special interest in muscle tearing because astronauts, retuning from weightless time in space, can experience a lot of it as they resume life in a gravity environment.

Collaborators on his study include Drs. Steven Vogel and Katsuya Miyake who direct and manage the MCG Cell Imaging Core Facility.