June 30, 2006

A Protein That Helps Turn Sound into Sense

Microscopic structures called stereocilia sit atop a hair cell Microscopic structures called stereocilia sit atop a hair cell. Tip links (arrows) connect shorter stereocilia to their taller neighborsNature Reviews Genetics 5, 489–98, copyright 2004 Macmillan Magazines Ltd.

Scientists say they may have uncovered a key player in how the body turns sound into sense — that is, how the vibrations called sound waves that pulsate through the air are turned into the words, music and clamor that our brains sense.

Dr. Douglas Kerr of The Johns Hopkins University School of Medicine and his colleagues, in work funded partly by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), cultured embryonic stem cells from mice with chemicals that caused them to grow into motor neurons, the nerve cells that send signals to muscle telling them to move. Just before transplantation, they added nerve growth factors to the culture. Most of the cells were also cultured with a substance that helps growing nerve fibers (called axons) overcome chemicals produced by myelin, the insulation around nerve fibers in the spinal cord, that normally inhibit their growth.

The cells were transplanted into eight groups of paralyzed rats. Each group received a different combination of treatments. Some received injections of a drug called rolipram, which is approved to treat depression and also helps counteract axon-inhibiting signals from myelin. Some also received transplants of neural stem cells that secreted a nerve growth factor that causes axons to grow toward it (called GDNF) into the sciatic nerve.

Three months after the transplants, the rats that had received the full cocktail of treatments had several hundred transplant-derived axons extending into the nervous system, more than in any other group. The axons in these animals reached all the way down the sciatic nerve to form functional connections with muscle in the lower leg. The rats showed an increase in the number of functioning motor neurons and an approximately 50% improvement in hind limb grip strength by 4 months after transplantation. In contrast, none of the rats given other combinations of treatments recovered lost function.

Follow-up experiments with GDNF treatment on only one side of the body showed that, by 6 months after treatment, 75% of rats given the full combination of treatments regained the ability to bear weight on the GDNF-treated limbs and to take steps and push away with the foot on that side of the body.

This study is the first to show that transplanted motor neurons can form functional connections with the adult mammalian nervous system. Much work remains to be done before a similar strategy could be tried in humans, however. “This study provides a 'recipe' for using stem cells to reconnect the nervous system,” Dr. Kerr says. "It raises the notion that we can eventually achieve this in humans, although we have a long way to go."

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