June 4, 2004 DURHAM, N.C. -- Two years after transforming human fat cells into what appeared to be nerve cells, a group led by Duke University Medical Center researchers has gone one step further by demonstrating that these new cells also appear to act like nerve cells.
The team said that the results of its latest experiments provide the most compelling scientific evidence to date that researchers will in the future be able to take cells from a practically limitless source -- fat -- and retrain them to differentiate along new developmental paths. These cells, they said, could then be used to possibly treat a number of human ailments of the central and peripheral nervous systems.
The results of the team's latest experiments were published June 1, 2004, in the journal Experimental Neurology.
Using a cocktail of growth factors and induction agents, the researchers transformed cells isolated from mouse fat, also known as adipose tissue, into two important nerve cell types: neurons and glial cells. Neurons carry electrical signals from cell to cell, while glial cells surround neurons like a sheath.
"We have demonstrated that within fat tissue there is a population of stromal cells that can differentiate into different types of cells with many of the characteristics of neuronal and glial cells," said Duke's Kristine Safford, first author of the paper. "These findings support more research into developing adipose tissue as a viable source for cellular-based therapies."
Over the past several years, Duke scientists have demonstrated the ability to reprogram these adipose-derived adult stromal cells into fat, cartilage and bone cells. All of these cells arise from mesenchymal, or connective tissue, parentage. However, the latest experiments have demonstrated that researchers can transform these cells from fat into a totally different lineage.
Earlier this year, Duke researchers demonstrated that these adipose-derived cells are truly adult stem cells. As a source of cells for treatment, adipose tissue is not only limitless, it does not carry the potentially charged ethical or political concerns as other stem cell sources, the researchers said.
"This is a big step to take undifferentiated cells that haven't committed to a particular future and redirect them to develop down a different path," said Duke surgeon Henry Rice, M.D., senior member of the research team. "Results such as these challenge the traditional dogma that once cells become a certain type of tissue they are locked into that destiny. While it appears that we have awakened a new pathway of development, the exact trigger for this change is still not known."
For their latest experiments, the researchers demonstrated that the newly transformed adipose cells expressed many similar cellular proteins as normal nerve and glial cells. Furthermore, they showed that the function of these cells is similar to nerves.
They exposed these newly formed cells to N-methyl-D-aspartate (NMDA), an agent which blocks the activity of the neurotransmitter glutamate and is toxic to nerve cells. In response to NMDA, the newly induced cells died, a response similar to normal nerve cells under the same conditions. Physiologic insults -- such as stroke -- can stimulate NMDA receptors on nerve cells, which can cause nerve cell damage or death by over-stimulating them.
"We found that these induced adipose cells demonstrated an excitotoxic response to NMDA that corresponded with a loss of cell viability, which suggests that these induced cells had formed functional NMDA receptors similar to those found on nerve cells," Rice explained. "Recent studies have demonstrated that NMDA receptor activation by glutamate may induce early gene transcription in developing neurons as well as determine the rate of neuronal proliferation in the brain. Our findings suggest that these induced cells exhibit characteristics similar to developing neuronal tissue."
Now that the researchers are confident that these newly induced cells appear to have similar functions as nerve cells, the next step will be to see how they respond when they are implanted a living animal model.
"While this is an important step forward, we still face many challenges to making use of these cells to treat human problems," said longtime collaborator Jeffrey Gimble, M.D., Pennington Biomedical Research Center at Louisiana State University System. "It seems probable that the potential first uses of such therapy would be in an acute setting, where you would have a window of opportunity right after a stroke, or spinal cord or peripheral nerve injury."
Until recently, it was believed that organisms were born with the full complement of neuronal cells, and that new neurons could not be formed. According to the researchers, the findings of their studies, as well as the experiments performed by others on bone marrow stem cells, opens up new possibilities for the treatment of nervous system disorders or injuries.
"We are trying to think about human disease in a new way," Gimble said. "Everyone is used to the concept of surgical, medical or pharmacological approaches to the treatment of disease -- we're looking at one of the next steps in biotechnology, which is using cellular therapies."
The current research was supported by the Owen H. Wangenstein, M.D., Faculty Research Fellowship of the American College of Surgeons. Other members of the Duke team included Shawn Safford, M.D., and Ashok Shetty, Ph.D.
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