Scientists have found a surprisingly simple way to turn mature cells back into a primitive state. Simply giving mouse blood cells an acid bath is enough to produce so-called pluripotent cells that can develop into any cell type in the body, they report in two new papers this week. The remarkable transformation contradicts many assumptions about cell biology and may ultimately lead to new ways to treat disease and injuries.
Scientists not involved in the work say the technique could be a game-changer if it pans out. "If this new approach is applicable to human cells, it would have great implications for regenerative medicine," says Hongkui Deng, a stem cell researcher at Peking University in Beijing. "It's quite surprising" that the technique "doesn't involve any genetic manipulation," says Rudolf Jaenisch, a developmental biologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.
In contrast to previous methods that involve complex and challenging laboratory techniques, the Japanese-American team of researchers took blood cells from newborn mice, briefly bathed them in a moderately acidic solution, and then returned them to a standard cell culture medium. A week later, cells that had survived the treatment had reverted into a pluripotent state.
The scientists took a cue form the world of plants. It has long been known that environmental stresses, including insufficient water or excessive heat, can convert somatic—or differentiated—plant cells in plants into immature cells that, under the right conditions, can develop into entire new plants. In 2008, Haruko Obokata, a stem cell scientist now at the RIKEN Center for Developmental Biology in Kobe, Japan, set out to see if animal cells might harbor a similar mechanism. She started subjecting mouse cells to a variety of stresses—such as squeezing, heating, or starving them of nutrients—for short periods of time.
Some of the surviving cells showed telltale biochemical signs of returning to an immature state. The most efficient way of reprogramming these cells turned out to be soaking them in a solution slightly less acidic than vinegar for 25 minutes and then returning them to a normal cell culture. After a week, about 20% of the cells had survived, and 30% of those had reverted to a pluripotent state that could differentiate into a variety of cell types. If placed in a conducive environment, clusters of these cells even grew into whole embryos.
The group calls the phenomenon stimulus-triggered acquisition of pluripotency (STAP). While STAP cells have many of the characteristics of embryonic stem (ES) cells, they did not initially grow and divide very well; they could be kept alive for only about 2 weeks. Further tweaking, however, produced STAP stem cells that can be kept alive and proliferating indefinitely.
While the scientists used white blood cells from newborn mice for most of the experiments, they showed that the technique also works on brain, skin, muscle, and other cells. Obokata says it can even produce STAP cells from adult mice, although the efficiency decreases with the age of the mouse. Obokata and her colleagues report the findings online today in two Nature papers.
"You just stress cells and [that changes] the state of pluripotentcy. It's a remarkable result," Jaenisch says. The method is so simple that it "will make reprogramming more accessible" to mainstream laboratories, adds Ernst Wolvetang, a stem cell scientist at the University of Queensland in St Lucia, Australia.
Previously, researchers have created pluripotent cell lines by isolating cells from early stage embryos; those cells are called ES cells. In 2006, Shinya Yamanaka of Kyoto University, showed that forcing the overexpression of proteins called transcription factors in differentiated cells can turn back the clock and make the cells behave like ES cells. Those cells are called induced pluripotent stem (iPS) cells. If the new STAP method can be extended to humans, it would sidestep the ethical objections to the use of embryos and the genetic mutations that sometimes occur in iPS cells.
These advantages could be very important for applications in regenerative medicine, in which scientists try to grow replacement tissues and treatments for genetic conditions such as diabetes and for degenerative diseases, such as Parkinson's and Alzheimer's.
"I see this as a new approach to generate iPS-like cells," says Yamanaka, who won the Nobel Prize in physiology or medicine in 2012 for developing iPS cells. But he cautions that if the STAP technique does work for human cells, it would still need to be compared to currently available methods.
Deng notes the results suggest that the natural reprogramming capability documented in plants "is somehow conserved between plant and mammalian cells." But it raises questions of how that capability is regulated in the body. The acids that digest food in mammalian stomachs are far stronger than the solution used in the STAP experiments. "I guess that our tissues have some mechanism to inhibit the reprogramming process in differentiated cells, but to prove that we need further studies," Obokata says.
Some animals are already known to have remarkable regenerative capabilities. In amphibians, such as newts and salamanders, cells at the site of an injury can de-differentiate to form entirely new limbs, eyes, and other body parts. Kuldip Sidhu, a stem cell specialist at the University of New South Wales in Sydney, Australia, says that understanding and controlling the mechanism that blocks or enables de-differentiation in humans could, in the distant future, "perhaps under some controlled conditions bring about tissue regeneration," within the human body.