Finding a cellular Neverland: How stem cells stay childlike

verted to their nave state and regained pluripotency.

Atsushi Suzuki, PhD., a former postdoctoral fellow in the Belmonte lab, was the lead author of both that and the present study. "It was exciting because nobody knew that 'reverse differentiation' occurred in ES cell cultures," he said referring to the first report. "And nobody knew how Nanog maintains an undifferentiated ES cell population."

Their current study explains how. When BMP turns ES cells into muscle it activates a protein called Smad1, a DNA-binding protein that, in opposition to Nanog, switches on genes responsible for muscle cell fate. Smad1 can only do this when assisted by generic factors known as co-activators, which stimulate gene expression.

The team found that in ES cells attempting to differentiate prematurely, Nanog actually binds to Smad1 protein and interferes with its ability to recruit those obligatory coactivators, thereby rendering Smad1 powerless to initiate muscle gene expression. With Smad1 out of the game and Nanog in full control, cells revert to their forever-young state.

"We found that in suitable conditions, differentiated cells are still capable of producing stem cells as descendants," says Suzuki. "The molecular mechanisms that we identified here might be used to regenerate stem cells from differentiated cells."

Identifying the Nanog/Smad1 feedback loop indeed has significant implications for regenerative medicine. Animals like salamanders readily regenerate severed limbs as adults, but mammals cannot. In fact, mammals have a limited repertoire of tissues they can regenerate, and some essential ones, such as nerves and cardiac muscle, are not on that list.

For human tissue regeneration to become a viable therapy for conditions like neurodegeneration or diabetes, clinicians will likely need to artificially manipulate factors that return adult brain or pancreatic cells to a cellular "Tir Nan Og" to restore adult

Contact: Gina Kirchweger
858-453-4100 x1340
Salk Institute

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