Current approaches for turning differentiated adult cells back into a stem–cell-like state involve messing with the nucleus in one way or another—either swapping out nuclear contents, a process called nuclear transfer, or inducing the expression of pluripotency genes. In two papers published in Nature today (January 29), researchers have developed an entirely different technique, this one based on exposure to environmental stimuli, including mechanical stress or a low pH.
“It’s pretty unexpected,” said stem-cell biologist Rudolph Jaenisch of the Whitehead Institute in Cambridge, Massachusetts, who was not involved in the research. “There’s no genetic manipulation, just some culture conditions, stress, to induce these changes. I think that’s quite remarkable.”
Researchers have known for some time that certain environmental conditions can reprogram plant cells, but animal cells have proven more stubborn. So Haruko Obokata at the RIKEN Center for Developmental Biology in Kobe, Japan and her colleagues tested various conditions to see if any could reset the differentiation state of mouse lymphocytes taken from the spleens of week-old animals. In one of the studies, they showed that dropping the pH of the cell culture from a little above 7 to 5.7 for 25 minutes resulted in the increased expression of the pluripotency gene Oct4 in a portion of the cells, suggesting they had reverted to a stem-cell state.
“They were stripped of their differentiation memory and reverted to a state of pluripotency that in many ways resembled what is seen in [embryonic stem] cells,” Obokata, the lead author of both papers, said during a conference call with reporters. “It was really surprising to see that such a remarkable transformation could be triggered simply by stimuli from outside of the cell.”
The researchers named their new reprogramming technique stimulus-triggered acquisition of pluripotency (STAP).
Jaenisch said that Obokata’s group did all the right assays to demonstrate that the cells are indeed pluripotent. “I think [the results] are quite convincing,” he told The Scientist. The researchers injected the reprogrammed cells into mouse embryos, where they contributed to the development of chimeric animals—more proof that the cells were truly pluripotent. In Obokata’s other study, performed by an overlapping group of colleagues, the team demonstrated that STAP cells can also develop into placental tissue—suggesting they are in a less mature state than induced pluripotent cells, which only contribute to embryonic tissue.
Shinya Yamanaka, a researcher at Kyoto University and the Gladstone Institutes and who first induced pluripotent stem (iPS) cells, said the findings are important for understanding nuclear reprogramming. “From a practical point of view toward clinical applications, I see this [as] a new approach to generate iPS-like cells,” Yamanaka said in an email to The Scientist. “If pluripotency is induced from human cells by a similar method, we will need to compare it with existing protocols.”
The mechanism underlying STAP is unknown. Sheng Ding, also at the Gladstone Institutes in San Francisco, said that he expects a number of labs to pick up on this new reprogramming approach to figure out how it works and to optimize the procedure. He wonders whether stress-induced reprogramming might have some relevance in tumorigenesis, given that stress and subsequent inflammation are tied to tumor development.
The potential for laboratory or clinical applications is also unclear. Obokata said STAP is much faster than inducing pluripotency by genetic manipulation, but a number of cells die in the process. After the low pH treatment, only about 20 percent of the cells survived, and of these, just 30 percent went on to express the fluorescent indicator of pluripotency. Still, this is quite a bit better than the usual 1 percent efficiency of creating iPS cells, although Obokata pointed out that she has not done a head-to-head comparison. “Whether technically this method is better, safer or more efficient, that’s a big question mark,” Ding told The Scientist.
H. Obokata et al., “Stimulus-triggered fate conversion of somatic cells into pluripotency,” Nature, 505:641-47, 2014.
H. Obokata et al, “Bidirectional developmental potential in reprogrammed cells with acquired pluripotency,” Nature, 505:676-80, 2014.