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What does mad cow disease have in common with stem cell research? MIT and Whitehead Institute scientists have found that the same protein that causes neurodegenerative conditions such as bovine spongiform encephalopathy (mad cow disease) is also important for helping certain adult stem cells maintain themselves.
"For years we've wondered why evolution has preserved this protein, what positive role it could possibly be playing," says MIT professor of biology and Whitehead member Susan Lindquist. "With these findings, we have our first answer."
Lindquist, Harvey Lodish (also an MIT biology professor and Whitehead member), and colleagues are co-authors on a paper to be published online in the Proceedings of the National Academy of Sciences during the week of Jan. 30.
For more than 10 years, researchers have known that a protein called PrP causes mad cow disease and its human equivalent, Creutzfeld-Jakob disease. PrP is a prion, a class of proteins that has the unusual ability to recruit other proteins to change their shape (PrP is shorthand for "prion protein."). This is significant, because a protein's form determines its function. When a prion changes shape, or "misfolds," it creates a cascade in which neighboring proteins all assume that particular conformation. In some organisms, such as yeast cells, this process can be harmless, even beneficial. But in mammals, it can lead to the fatal brain lesions that characterize diseases such as Creutzfeld-Jakob.
Curiously, however, PrP can be found throughout healthy human bodies, particularly in the brain where it's highly abundant. In fact, it's found in many mammalian species, and only on the rarest occasions does it result in disease. Clearly, scientists have reasoned, such a widely conserved protein also must play a positive role.
Chengcheng Zhang, a postdoctoral researcher in Lodish's lab, was studying hematopoietic (blood forming) stem cells in mouse fetal tissue when he discovered that PrP was expressed abundantly on the surfaces of these stem cells. "I found that while not all blood cells with PrP on their surface were stem cells, any cell that lacked PrP was definitely not a stem cell," says Zhang.
Zhang teamed up with the Lindquist lab's graduate student Andrew Steele, an expert in prions, to discover what role PrP might play in stem cell biology. Zhang and Steele took bone marrow from mice in which PrP had been knocked out, and transferred that marrow into normal mice whose blood and immune systems had been irradiated. The new bone marrow took hold, and these mice flourished, although all their blood cells lacked PrP. Zhang and Steele continued the experiment, this time taking bone marrow from the newly reconstituted mice, and transplanting it into another group of mice. They repeated this process again and again -- transplanting bone marrow from one group of mice to another like passing a baton.
Soon they noticed that with each subsequent transplant, the stem cells began to lose their ability to reconstitute. Eventually, the scientists ended up with mice whose hematopoietic stem cells completely lacked the ability to generate new cells. However, in the control group, where they mimicked the experiment with bone marrow abundant with PrP, each transplant was as good as the next, and at no point did stem cells lose their efficacy.
"Clearly, PrP is important for maintaining stem cells," says Lodish. "We're not sure yet how it does this, but the correlation is obvious."
"PrP is a real black box," Lindquist says. "This is the first clear indication we have of a beneficial role for it in a living animal. Now we need to discover its molecular mechanism."
This research was funded by the National Science Foundation, the National Institutes of Health, the Ellison Medical Research Foundation and the Leukemia and Lymphoma Society.