“Don’t judge a cell by its cover” has turned out to be sage advice for stem cell scientists. They have discovered a new class of cells, generated from mouse tissue, that can be reprogrammed to become almost any cell in the body.
Called F-class cells for their fuzzy appearance in a petri dish, they were probably overlooked in the past because they don’t look like ordinary stem cells. But experiments suggest they have similar powers of flexibility. The F-class cells are described in two papers appearing December 11 in Nature by a worldwide stem cell research collaborative called Project Grandiose.
These cells aren’t as sticky as typical stem cells and don’t grow in smooth, compact clumps. Their un-stickiness means that F-class cells can be grown by the billions in a flask rather than in single layers on a petri dish. That quality will make experiments easier, possibly leading to new drugs or even engineered replacements for diseased organs or tissues.
“This is a real conceptual advance,” says stem cell biologist Jun Wu of the Salk Institute for Biological Studies in La Jolla, Calif., coauthor with Salk’s Juan Carlos Izpisua Belmonte of a Nature commentary on the new research. There’s still much work to be done, cautions Wu. For starters, scientists need to determine if F-class cells can be generated from human cells. But the discovery is exciting, he says. It’s the first case of culturing a new kind of stem cell in the lab, and the method used to coax the F cells into being offers a new way to engineer stem cells from ordinary tissue.
Stem cells, defined by their dual ability to renew themselves exactly and, at the right time, to specialize into all sorts of cell types, come from two primary sources. One is embryonic cells found in the inner layer of the blastocyst, the small mass of cells created when sperm meets egg. Scientists can prompt these embryonic stem cells into specializing — becoming heart cells that pump blood, for example, or brain neurons. But research on embryonic stem cells has been roiled in ethical debates concerning the use of embryos. Induced pluripotent stem cells, called iPS cells, provide a second source of stem cells. Scientists create iPS cells by coaxing adult mouse skin cells into an embryonic-like state. This is managed by dosing the cells with a cocktail of four particular proteins that somehow reprogram the cell.
The new F-class stem cells also are produced from mouse skin cells, but differ from standard iPS cells. Typically, to prod a skin cell into becoming a stem cell, scientists deliver genes for making the four reprogramming proteins into the host skin cell. Once it becomes a stem cell, the host cell normally shuts off the genes controlling the reprogramming proteins. But researchers led by stem cell scientist Andras Nagy of Mount Sinai Hospital in Toronto used a different system to deliver the reprogramming proteins. This approach evades the host cells’ ability to shut protein production down. Instead the researchers control the on/off switch with a drug called doxycycline.
After several days in a dish with doxycycline and the reprogramming proteins running on high, the mouse skin cells started to clump into colonies. Since the colonies didn’t look like smooth, shiny stem cells and the reprogramming proteins were still turned on, many scientists probably wouldn’t have looked at them twice, says Nagy.
“Most people would have said, ‘this is not what we are looking for,’” he says. “But we decided to pick our cells blindfolded, to use everything that was growing.” When the scientists investigated whether these strange fuzzy cells were indeed stem cell–like, the F cells passed two standard stem cell tests: They could be prompted into becoming different types of cells and they form a specific kind of tumor containing many different tissue types.
By manipulating the amount and timing of exposure to the reprogramming proteins, and the media that the cells were grown in, the scientists could convert the F cells into a more ordinary iPS cell state. They could also convert those iPS-like cells back into the F cell state. An exhaustive analysis of molecular and gene activity in the two states suggests that changes in DNA packaging, which result in different genes being turned on and off, are behind the differences. These analyses are described further in three additional papers by Project Grandiose in the December 11 Nature Communications.
There’s still a lot to be done. Not only are experiments needed with human cells, but researchers have also not yet made fully functioning cells from the F cells — liver cells that can metabolizes toxins, for example. But the research offers a new approach to making stem cells and is a major first step in characterizing how cellular reprogramming happens, says Wu. “It opens the door to engineering cells,” he says. “We might be able to customize these cells in the future.”