Researchers at the School of Medicine have identified a new protein critical to the production of induced pluripotent stem cells, or iPS cells.

The protein, NKX3-1, has previously been shown to play a role in prostate development and tumor suppression. It can substitute for one of the four proteins first identified in 2007 by stem cell researcher Shinya Yamanaka, MD, PhD, as sufficient to prod mature cells like those in the skin or blood to become iPS cells — a transformation known in the stem cell world as reprogramming.

The discovery creates a peephole into the black box of cellular reprogramming and may lead to new ways to generate iPS cells in the laboratory. It was made possible by the use of a unique laboratory model for reprogramming that tightly synchronizes the earliest steps of the process. “This is a crucial regulator that would not have been discovered any other way,” said Helen Blau, PhD, professor of microbiology and immunology. “It appears within two hours of the initiation of reprogramming, and then it’s gone. But it’s absolutely critical. If we eliminate it, reprogramming doesn’t happen.”

Blau, the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Foundation Laboratory for Stem Cell Biology, is the senior author of the research, which was published online July 16 in Nature Cell Biology. Postdoctoral scholar Thach Mai, PhD, is the lead author.

The ability to reprogram mature cell types, such as skin cells, into pluripotent stem cells by the addition of just four proteins, called Yamanaka factors, captivated the scientific world and led to a Nobel Prize in 2012 for Yamanaka. Since then, countless researchers worldwide have used the technique to create iPS cells for study or potential clinical use.

Hopes for safer reprogrammed cells

The four Yamanaka factors — Oct4, Sox2, cMyc and Klf4 — were identified because they are highly expressed in embryonic stem cells in mice and humans. Exposing mature cell types to these factors makes them regress in their development and, eventually, behave like stem cells, even beginning to express Oct4 on their own. There are concerns about this process, however, because cMyc and Oct4 are oncogenes that can cause cancers when overexpressed in normal cells. Researchers believe an understanding of how reprogramming occurs might allow them to identify new ways to generate stem cells that are safer for clinical use.

Unfortunately, much of what goes on during the first hours of reprograming has remained a mystery, in part because only about 1 in 1,000 cells treated with the factors successfully undergoes the transition. Furthermore, those that do, do so on their own erratic schedule.