By Alison Abbott
Given the right conditions, any adult cell can be coaxed into becoming stem-cell like, according to a team of researchers based in the United States. The team, led by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, were also able to speed up the process, cutting the time required for cells to become stem-cell like by around half.
The results are good news for those battling to work out the complex biology of these cells, know as induced pluripotent stem (iPS) cells -- which can develop into any other cell type. So far, the experimental conversion or 'reprogramming' of adult cells into iPS cells has been slow and inefficient, leaving some wondering whether only an elite subset of adult cells could make the switch.
Scientists hope that they will one day understand iPS cells well enough to substitute them for embryonic stem cells, which are ethically controversial, for use in regenerative medicine.
Jaenisch and his colleagues developed a sophisticated system to study reprogramming. It involves using genetically identical mouse immune cells that contain additional copies of four genes required for reprogramming. The genes include switches that allow them to be turned on by the addition of a drug.
Paths to pluripotency
In the first in a series of experiments, the researchers grew individual immune cells, switched on their reprogramming genes and allowed them to continue growing and dividing. The team monitored how quickly the cells divided, and at what stage they began to produce a chemical signal that indicated they had become iPS cells. From time to time, the authors also checked some of the cells to make sure they really were pluripotent -- for example, checking whether they could form teratomas, a type of tumour made up of many different kinds of cell.
Some of the cell populations began to signal after just two weeks. Others took longer -- up to 18 weeks -- but only 8% of the populations failed to generate iPS cells by this time. "Essentially, all cells have the potential to become pluripotent," Jaenisch says.
The authors didn't get many clues about why some cells take longer than others to generate iPS cells. But they noted that, for their immune cells, the rate of cell division was not relevant because all of the cells divided at roughly the same rate. "It is something that seems to happen to the cells under these conditions stochastically -- that is, in a continuous, but probabilistic fashion," says Jaenisch.
One factor that the scientists believe might have a role in accelerating some cells' path to pluripotency is genes such as NANOG. When the team increased expression of this gene, the rate of division in the immune cells did not change significantly, but the cells did require fewer cell divisions -- and so less time -- to become pluripotent.
In other experiments, the researchers were also able to cut the time required to generate iPS cells by increasing the expression of cancer-related genes, such as p53, which have recently been found to affect the efficiency with which adult cells can be reprogrammed (see 'Immortality improves cell reprogramming'). Activating molecular pathways involved in cancer increased the rate at which the immune cells divided, and the rate of reprogramming increased in parallel: nearly all cell populations generated iPS cells within eight weeks.
Cells with and without cancer-gene modification produced iPS cells after the same number of cell divisions. Jaenisch suspects that reprogramming involves a series of epigenetic events -- whereby DNA is modified by chemical signals to control the rate of particular genes' expression -- and that these mostly occur as cells are dividing. So it makes sense that when cells divide more quickly, as cancer cells do, they also become pluripotent more quickly, he says.
The team's clever methodology broke through the technical barriers that had been holding the field back, says Juan Carlos Izpisúa Belmonte of the Salk Institute for Biological Studies in La Jolla, California.
"Showing that all cells, or at least these immune cells, may be capable of being reprogrammed solves a problem we have been struggling with for a long time," he adds. "And demonstrating that there are two ways for the cells to reprogram -- one dependent on cell division, the other not -- opens new prospects for analysing the many other problems of stem-cell biology we are still struggling with, including the efficiency and quality of iPS generation."