Apr. 15, 2004 HOUSTON -- Taking a major step forward in stem cell biology, researchers at The University of Texas M. D. Anderson Cancer Center have turned muscle progenitor cells -- stem cells that are "committed" to becoming muscle tissue -- into cells that look and act like neurons (nerve cells).
Using an artificial gene they created, the researchers "switched on" a panel of genes that are normally silent in the muscle cells, causing them to morph into cells that show biochemical, physiological, and structural properties of neurons.
The researchers say the advance, published in the April 15 issue of Genes and Development, provides evidence that stem cells could be profoundly "flexible" -- able to develop into different cell types.
"It is amazing to know that the fate of a cell can be changed by a single molecule," says the lead author Sadhan Majumder, Ph.D., an associate professor in the Department of Cancer Genetics. "If we can redirect muscle progenitor cells to become cells that have the properties of neurons, it may be possible to use the same kind of technique to potentially change the fate of other stem cell types."
The work was conducted in laboratory cell cultures of "myoblasts," the progenitor muscle stem cells, and the new cells were then injected into the brains of healthy mice, where the cells did not cause any ill effects. Majumder says the next phase of the research is the "big test, whether these new cells can replace neurons that are damaged inside the body. That would be a remarkable step towards neuroregeneration."
To date, nerve cell regeneration from nonneural stem cells primarily has been studied using bone marrow cells, but mouse experiments that suggested these stem cells could convert to nerve cells have been controversial. Some investigators suspect that manipulated bone marrow cells are either contaminated with neural stem cells or get fused with neuronal stem cells present in the brain, and so only appeared to become nerve cells.
To avoid any issue with such potential contamination or fusion, Majumder and his colleagues chose to use for their experiment a line of homogenous cultured myoblasts that has long been used for muscle differentiation research.
Majumder devised the artificial gene that played a key role in the experiments several years ago when studying how neural stem cells mature into neurons. Neuronal stem cells go through a series of steps before they differentiate into neurons, and each step is initiated by expression of different sets of genes. The last step, in which a large number of genes are activated, is only made possible when a repressor gene -- a kind of brake known by the acronym REST/NRSF -- is absent, allowing the set of genes to be turned on.
At the time, Majumder wanted to know what would happen if those particular genes -- the last to be activated were turned on first, by-passing the normal development process. So he and his colleagues created a new gene (REST-VP16) that was modeled on the natural repressor gene, but actually worked to turn the genes on. "We converted what is normally a brake into a gas pedal," he says.
So now the researchers tested what would happen when myoblasts, which are normally committed to become muscle, were genetically altered to express the new gas pedal gene attached to a molecular switch. To his delight, the experiment worked. When REST-VP16 was turned on in myoblasts, it was enough to block the cells' entry into the muscle differentiation pathway and caused them to show neuronal properties.
"If you keep the REST-VP16 gene off, the myoblasts became muscle," he says. "If you turn the gene on, the cells didn't even enter the muscle differentiation pathway. Instead, they looked like neurons, turned a large number of neuronal genes on and showed physiological activities of neurons.
"The study not only suggests that "the fate of stem cells can potentially be altered," says Majumder, but provides an experimental way of driving those changes.
Working with Majumder were M. D. Anderson researchers Yumi Watanabe, Ph.D., Sei Kameoka, Vidya Gopalakrishnan, Ph.D., Kenneth Aldape, M.D., Zhizhong Pan, Ph.D., and Frederick Lang, M.D. The study was supported by grants from the National Cancer Institute. Watanabe is now at Kyoto University and Kameoka is at Harvard University.
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