In 2006, Shinya Yamanaka, MD, PhD, turned the stem-cell world upside down when he showed it was possible to take mature, specialized cells such as those found in skin and convert them to a pluripotent state simply by exposing them to a few key proteins. The discovery earned Yamanaka the Nobel Prize in Physiology or Medicine in 2012 and sparked an explosion of stem-cell science.
Although the exact steps of the reprogramming process are unknown, scientists have thought it proceeded mostly as a two-step pathway that essentially rewinds the march to specialization that normally occurs during development. Now Marius Wernig, MD, and his colleagues at the Stanford Institute for Stem Cell Biology and Regenerative Medicine have uncovered an intermediary state through which the cells must pass to successfully acquire pluripotency (a term that describes a cell's ability to become nearly any cell type in the body). The researchers published their findings in today's Nature.
As Wernig described in my article on the research:
This [finding] was completely unexpected. It’s always been assumed that reprogramming is simply a matter of pushing mature cells backward along the developmental pathway. These cells would undergo two major changes: they’d turn off genes corresponding to their original identity, and begin to express pluripotency genes. Now we know there’s an intermediary state we’d never imagined before.
Cells in this "bridge" state express cell surface markers that are distinct from those found on fibroblasts (the starting cell type) and on successfully reprogrammed iPS cells. They also express specific transcription factors that likely contribute to the cells' progression through the reprogramming process.
The researchers believe it may be possible to increase the efficiency of reprogramming in cells that typically resist the process (these cell types include highly specialized cells or cancer cells). But they're more excited about peeking into the inner workings of a transformation that's been both revolutionary and mysterious.
“We’re learning more and more about how cells accomplish this really unbelievable task of reverting to pluripotency,” Wernig told me. “Now we know that the cell biology of this process is novel, and this intermediary state is unique.”
Previously: Congratulations to Marius Wernig, named Outstanding Young Investigator by stem cell society, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Human neurons from skin cells without pluripotency?
Photo by Alexis R