Wed Feb 18th, 2004
Scientists have created an unlimited supply of a type of nerve cell found in the spinal cord - a self-renewing cell line that offers a limitless supply of human nerve cells in the laboratory. Such a supply has long been one goal of neurologists anxious to replace dead or dying cells with healthy ones in a host of neurological diseases.
In this study, appearing in the March issue of Nature Biotechnology, the scientists then used the cells to partially repair damaged spinal cords in laboratory animals, re-growing small sections of the spinal cord that had been damaged. Doctors emphasize that tests in people with damaged spinal cords or other neurological conditions are a long ways off.
The researchers, led by neurologist Steven Goldman, M.D., Ph.D., of the University of Rochester Medical Center, created the unique cells by introducing a gene called telomerase, which is responsible for the ability of stem cells to live indefinitely, into more specialized "progenitor" cells. In normal development, these progenitor cells give rise to very specific types of spinal neurons, but they do so for only short periods of time, because they lack the ability to continuously divide. With the newly added telomerase gene, the spinal progenitor cells were able to continuously divide while still producing only specific types of neurons. The outcome was a line of immortal progenitor cells, capable of churning out human spinal neurons indefinitely.
While stem cells receive a great deal of attention as a possible source of life-saving treatments, progenitor cells offer great potential, Goldman says. To be sure, progenitor cells lack a key feature of stem cells: Their potential to become nearly any type of cell. But what progenitor cells lack in potential, they make up for with commitment: They have already "decided" exactly what type of cell to become in the body, an advantage when treating a disease where one specific cell type is at risk. A patient with Parkinson's disease, for example, may only needs to replace dopamine-producing neurons, while in patients with multiple sclerosis, only cells that produce myelin need be restored.
Since committed progenitor cell normally can divide for only a limited number of times, until now scientists have been unable to produce enough to make a difference clinically. Goldman's team solved the problem by introducing the gene for telomerase at just the right moment in the cell's lifetime, when it has committed to a particular spinal cell type, thus immortalizing the cells at this key juncture. The result was a line of immortal progenitor cells giving rise only to human spinal neurons, including both motor neurons and interneurons, two of the most clinically important cell types of the spinal cord.
"The progenitor cells are immortalized at a stage when they only give rise to the type of neuron we want, thus becoming an ongoing source of these neurons," says Goldman, who is professor of Neurology and chief of the department's Division of Cell and Gene Therapy.
Goldman's team propagated these cells for over two years, the longest anyone has ever maintained such a line of neuronal progenitor cells. With these select neurons in hand, Goldman's colleagues, led by Maiken Nedergaard, M.D., Ph.D., professor of Neurosurgery, then injected the modified progenitors into rats and found that the cells replaced damaged parts of the spinal cord with new nerve cells.
A key finding was the lack of tumors, or any tendency toward tumor growth, says Goldman. Telomerase is one of the ingredients that cancer cells needs to survive, and previous work had indicated that turning the gene for telomerase on could heighten the risk of tumors. But the group followed the rats closely for six months, and the cells in the laboratory for two years, and found no increase in tumors or a tendency to develop into tumors. After about a month, the cells in the animals stopped proliferating, as neurons in the spinal cord normally do.
Since the spinal cord is made up of several types of neurons, the group now is creating and working with other cells that would create other types of neurons necessary to repair spinal cord tissue.
"This work is the culmination of six years of work, and it will be many more years before an approach like this can be tried in human patients. But the promise is extraordinary," says Goldman, whose project was funded by Project ALS and the Christopher Reeve Paralysis Foundation.
From Rochester, other authors include Martha Windrem, Ph.D. Other authors
include Neeta Roy, Takahiro Nakano, H. Michael Keyoung, William Rashbaum,
M. Lita Alonso, Jian Kang, Weiguo Peng, and Jane Lin of Cornell, and Melissa
Carpenter of Geron Corp., who is now at the Robarts Research Institute
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