Recipe for cell reprogramming adds protein

A drug-like molecule called Wnt can be substituted for the cancer gene c-Myc, one of four genes added to adult cells to reprogram them to an embryonic-stem-cell-like state, according to Whitehead researchers.

Researchers hope that such embryonic stem-cell-like cells, known as induced pluripotent (IPS) cells, eventually may treat diseases such as Parkinson's disease and diabetes.

Demonstrated in mice, the elimination of c-Myc represents an important step in creating IPS cells in a manner that in the future may be applied to human therapeutics.

"IPS cells hold great potential for future medicine, but we must learn how to generate these cells in a manner that is safe for clinical therapies," says Whitehead Member Richard Young. "This advance in reprogramming is one key step toward that goal."

"This is a good sign for the possible replacement of the other three genes used to reprogram cells," says Ruth Foreman, a MD/PhD student in the lab of Whitehead Member Rudolf Jaenisch and a lead co-author on the paper, published online in Cell Stem Cell on August 6. The other lead co-authors are Alex Marson, an MD/PhD student in the labs of Jaenisch and Whitehead Member Richard Young, and Brett Chevalier, a research scientist in the Young lab.

"IPS cells hold great potential for future medicine, but we must learn how to generate these cells in a manner that is safe for clinical therapies," says Young, who is also a professor of biology at Massachusetts Institute of Technology. "This advance in reprogramming is one key step toward that goal."

Currently, IPS cells can be created by reprogramming adult cells through the use of viruses to transfer four genes (Oct4, Sox2, c-Myc and Klf4) into the cells' DNA. The activated genes then override the adult state and convert the cells to embryonic-like IPS cells.

However, this method poses significant risks for potential use in humans.

First, the viruses employed in the process, called retroviruses, are associated with cancer because they insert DNA anywhere in a cell's genome, thereby potentially triggering the expression of cancer-causing genes, or oncogenes. Second, c-Myc is a known oncogene whose overexpression can also cause cancer. For IPS cells to be employed to treat human diseases such as Parkinson's, researchers must find safe alternatives to reprogramming with retroviruses and oncogenes.

Earlier research has shown that c-Myc is not strictly required for the generation of IPS cells. However, its absence makes the reprogramming process time-consuming and highly inefficient.

To bypass these obstacles, the Whitehead researchers replaced c-Myc and its retrovirus with a naturally occurring signaling molecule called Wnt3a. When added to the fluid surrounding the cells being reprogrammed, Wnt3a promotes the conversion of adult cells into IPS cells.

"We're not sure if the Wnt molecule is doing the same thing as c-Myc or complementing c-Myc's activity," says Chevalier. "But it does increase stem cell growth similar to c-Myc."

"This is a good start toward using external cues instead of genetic manipulation to reprogram cells," says Marson. "But we still need to eliminate the need for retroviruses for the three other genes."

Although the technique is promising in mouse cells, its potential applications in humans have not been studied, emphasizes Jaenisch, who is also a professor of biology at MIT. "Is the same pathway acting in the human system and can Wnt molecules be used to reprogram human cells?" he asks. "We don't know, but I think those are very important questions to investigate."

This research was supported by the National Institutes of Health.

Written by Nicole Giese.