LONDON - The prospects for novel therapies that require stem cells continue to brighten with a report this month that neural stem cells can be induced to turn into muscle cells.

The Italian researchers who made this discovery now want to find out if they can induce stem cells from blood or muscle to turn into neural stem cells instead. If they are successful, they would solve at a stroke one of the obstacles blocking progress towards cell therapy of neurological diseases such as Parkinson's disease, for example.

Angelo Vescovi, co-director of the Stem Cell Research Institute at the Hospital San Raffaele in Milan, Italy, told BioWorld International: "Our study demonstrates that human embryonic neural stem cells can undergo the same kind of conversion into muscle cells as do neural stem cells from mice. This is very important from the point of view of the potential therapeutic application of this work because it is possible to do it using established embryonic cell lines from humans, whereas it has never been possible to establish stem cells from the adult human brain and expand them to the extent where you can do an experiment with them."

Vescovi, together with colleagues based in Milan, Rome and Pavia in Italy, and at the University of Washington in Seattle, describe their results in a paper in the October edition of Nature Neuroscience titled "Skeletal myogenic potential of human and mouse neural stem cells." The first author is Rossella Galli, also at the Stem Cell Research Institute.

During the early 1990s, Vescovi was one of a team of researchers who discovered that some cells present in the adult brain were able to differentiate into several different types of brain cells, given the appropriate conditions. He also noted that examination of a type of human brain tumor called medulloblastoma had shown the presence of not only several different types of brain cells, but also, in some cases, muscle cells. He said, "I initially, and then with others, argued that under certain curious circumstances, it may be possible for neural stem cells to generate other cell types which do not normally originate in the brain."

Other research took priority for a while, but in 1997 Vescovi and colleagues picked up the project again, conducting experiments to find out if neural stem cells could indeed make other kinds of cells. In January 1999, they published a paper in Science showing that neural stem cells could differentiate into blood cells.

"This paper challenged one of the central dogmas of embryology - that once cells are compartmentalized into the different layers of the embryo, the endoderm, the mesoderm and the ectoderm, they cannot give rise to cells from a different layer," Vescovi said. "Yet we showed that they could because brain cells and blood cells are derived from different embryonic germ layers."

The paper in Nature Neuroscience provides a similar challenge to the dogma, because muscle cells, like blood cells, are derived from the mesodermal layer, whereas brain cells differentiate from cells from the ectoderm.

For the latest studies, the researchers isolated single stem cells from the adult brain of the mouse and cultured these either alone or with myoblasts (cells which turn into muscle fibers). For one of the key sets of experiments, the team used brain cells from transgenic mice that had been manipulated to carry a marker gene under the control of the promoter for myosin (a contractile protein made by muscle fibers). If the neural stem cells turned into muscle cells, the promoter for myosin would turn on production of the marker gene.

"This system allowed us to detect conversion of the neural stem cells into muscle cells, and we could count how many of these cells had been induced to become muscle cells," Vescovi said. He stressed that electron microscopy had shown that the muscle cells were functional. "As well as expressing markers characteristic of muscle cells, we could see that sarcomeric units with M and Z bands - in other words, the contractile fibers that allow muscle cells to contract - were present in the cytoplasm of these cells," he said.

The team found that the neural stem cells would only differentiate into muscle cells if they were in contact with myoblasts. Conversely, if the neural stem cells were clustered together, they retained their neural identity.

Having obtained these positive results, the group repeated the experiments using neural stem cells from human embryonic cell lines. "We did the same experiments using myoblasts - and it worked," Vescovi said.

He and his colleagues went on to assess whether adult neural stem cells from mice, and embryonic stem cells from humans, could become converted to muscle cells in vivo. For this study, the team used mice which had received an injection of cardiotoxin in one of their leg muscles. This caused damage, followed by regeneration of the damaged area - including formation of myoblasts.

Vescovi said, "We found that both the human and the mouse cells aquired the identity of muscle cells when injected into the damaged muscle following the recovery phase."

The researchers now plan to find out if they can induce stem cells from outside the central nervous system, such as stem cells from blood and muscle, to differentiate into neural stem cells. They also want to identify which molecules are involved in the process by which a stem cell destined to become one type of differentiated cell becomes able to differentiate into another type.

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