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Of mollusks, mice and stem cells
Human stem cells, it turns out, aren’t entirely human. At least not in the U.S., where human stem cell lines have been grown using “feeder” cells, derived from mice, to preserve their potency.
While suitable for basic research, ultimately these cells are too risky for medical use because they may be contaminated by mouse-associated viruses.
But there may be a work-around.
Rockefeller’s Ali Brivanlou, working in collaboration with French and Greek scientists, has devised an alternate system for maintaining existing or new human stem cell lines that’s based on a Mediterran-ean shellfish.
It works like this: a new compound, derived from the purple dye of a marine red mollusk — called 6-bromoindirubin-3'-oxime or by its working acronym, “BIO” — has been shown to activate a crucial gene expression mechanism, called the Wnt signaling pathway, in embryonic cells.
The Wnt pathway, in turn, keeps stem cells in an active, undifferentiated state. As long as Wnt is active, stem cells remain stem cells. Turn it off, and they are free to specialize — to become any of the dozens of types of tissues that make up the human body. In order to be truly useful, cultured stem cells must be capable of self-renewal in an undifferentiated state.
“We know precisely how this compound works — that is, on which enzymes and pathways — and that it is very controllable,” says Brivanlou, who is head of the Laboratory of Molecular Vertebrate Embryology. “This knowledge makes the compound useful not only in stem cell research but also, as we are already seeing in the lab, in numerous other research areas.”
As is often the case with discoveries, this one was something of an accident. Red mollusks were not on Brivanlou’s scientific radar screen until early in 2003, when Laurent Meijer, a biochemist from the Roscoff Marine Biology Institute in France, came to Rockefeller for a sabbatical in Rockefeller Nobel laureate Paul Greengard’s Laboratory of Molecular and Cellular Neuroscience. Meijer asked Brivanlou to test a new compound that he and a Greek collaborator, Leandros Skaltsounis, had recently isolated from red mollusks. The two scientists wanted to know whether the compound inhibited GSK-3, an enzyme associated with both the Wnt pathway and several neurodegenerative disorders.
“Protein kinases like GSK-3 are very promising targets for the discovery of new therapeutic agents,” says Meijer. “In particular, pharmacological inhibitors of GSK-3 have great potential for application to treat Alzheimer’s disease as well as sleep disorders and depression.”
Brivanlou and Alin Vonica, a postdoc in his lab, confirmed that the synthetic compound mimicked Wnt activation. And in the process, they discovered that the compound arrested differentiation of stem cells in frog embryos.
Thus far, Brivanlou has applied the BIO compound to frog, mouse and NIH Registry human stem cells, with favorable results. So far, it has demonstrated superior stability over other methods designed to circumvent the need for mouse feeder cells. And the stem cells appear to progress and differentiate normally after the compound is removed.

January 30, 2004



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