Stretching Nerve Cells For Transplant

Most research toward nerve repair has taken one of two approaches: enticing cells to grow on their own, and attempting to span the injury site with cell transplants. So far, neither has proved medically useful.

In the April issue of the journal Tissue Engineering, a team from the University of Pennsylvania reported a fundamentally new approach. By stretching nerve cells a tiny bit at a time, they produced cells up to 1 centimeter long (about half an inch), an extraordinary distance at the cellular level.

Douglas H. Smith, M.D., and John A. Wolf, B.S., of the Department of Neurosurgery and Whitaker Investigator David F. Meaney, Ph.D., of the Department of Bioengineering said this is the first evidence that the connecting threads between nerve cells will grow when stretched. They also found no reason why the cells would not grow longer if they kept pulling on them.

Their findings appear consistent with what happens to the central nervous system in children as they mature. Nerve cells grow and multiply and connect with one another by way of long extensions called axons. Most of this activity occurs in the embryo. By the time a child is 2, new connections stop forming. But, of course, children continue to grow.

"In a way, stretching is akin to how nerve cells grow in developing children," Smith said. "As they get taller, their axons get longer."

The researchers believe that axons grow from their midsections in response to the mechanical tension of the growing organism. "Growth must occur by structural reorganization and extension of the central length of the axon," they reported. "We hypothesize that continuous tensile forces along axons trigger this growth in length."

On this premise, the group designed experiments to evaluate mechanical stretch-induced growth of axons by placing continuous mechanical tension on axons connecting two groups of central nervous system neurons.

First the neurons were cultured for three weeks on a custom-built device that provided two adjacent membranes on which to grow. The cells sent out axons in all directions and made numerous connections. Then the two membranes were slowly separated at a rate of about 1 millimeter a day for more than a week. Axons that connected cells on one membrane with cells on the other began to lengthen in response to the mechanical tension.

In more than 20 separate studies, thick bundles of axons would bridge the gap between the two separating membranes. The axons began as a jumble, like spaghetti. As they stretched, they lined up like harp strings. The largest bundles comprised well more than 1,000 axons. For each colony of stretched cells, as many as 300 bundles---a total of 300,000 axons---crossed the widening gap. These are believed to be sufficient numbers to restore spinal cord function, Meaney said.

A number of issues will have to be addressed in exploring possible human treatments, and there is no guarantee of success. Meaney said research is underway along two lines: exploring the possibility of performing nerve grafts to repair spinal cord damage, and basic studies into the biological mechanisms involved in stretch-induced growth.

The initial experiments used several different cell types, including human neurons from a cell culture that is currently being used in a Food and Drug Administration-approved clinical trail for treating strokes. The fact that the cells are already approved for FDA clinical trials may hasten their use in spinal cord trials as well.