In a step that has implications for stem cell research, human biology and the treatment of disease, researchers in Japan and at Harvard University have managed to turn adult cells back into flexible stem cells without changing their DNA.
The researchers discovered that they could put cells in various challenging circumstances – including in acidic solutions and under physical pressure – and turn mature blood cells into cells that were capable of turning into virtually any cell in the body.
The research, published today in the journal Nature, was in mice. If it can be repeated in people, it has the potential to transform research using stem cells to treat disease, and it may lead to a new understanding of how the body heals from injury, said Charles Vacanti, the Harvard Medical School stem cell and tissue engineering biologist who led the research.
Biology textbooks say that once a cell matures to serve a specific role, like, say a red blood cell, it can never go back into a less mature state. Vacanti and his colleagues say their new research upends that dogma.
"This study demonstrates that any mature cell when placed in the right environment can go back, become a stem cell, which then has the potential to become any cell needed by that tissue," said Vacanti, also of Brigham and Women's Hospital in Boston.
He believes that that process happens naturally in the body after injury, and the more significant the injury, the farther back these cells will revert. "With a very significant injury, you will cause it to revert clear back to what is basically an embryonic stem cell," he said.
In an early embryo, all cells are stem cells, capable of turning into any cell in the body. As the fetus develops, those cells differentiate into cells with specific functions in muscles, blood, organs, etc. Some of those mature cells develop diseases and injuries. The promise of stem cells – as yet largely unrealized – is to provide patients with healthy versions of their own cells that can then repair damage and reverse disease.
Most people are familiar with stem cell research because until 2006, embryos had to be destroyed to study them.
Then, Japanese researcher Shinya Yamanaka developed a strategy for tinkering with adult cells, reverting them to stem cells. This has led to dramatic advances in the field, but because his approach required changes to the genetic material in a cell's nucleus, researchers have been anxious about using these cells in patients.
If stem cells can be created simply by bathing adult cells in a low-pH solution or putting them under physical pressure, that would make research simpler and more applicable to the real world, according to several researchers not involved in the new work.
"It would be a game changer in the sense that we think of cell reprogramming as an artificial process that requires complicated genetic manipulation," said Ricardo Dolmetsch, Global Head of Neuroscience at the Novartis Institutes for Biomedical Research, a Cambridge, Mass.-based arm of the drug company. "From a practical point of view, if all it takes is a a change in pH and a change in cell culture conditions, then this will make the process of making stem cells a lot simpler and lot easier to scale."
In the two papers published today, the researchers, including several from the RIKEN Center for Developmental Biology in Kobe, Japan, produced cells they call stimulus-triggered acquisition of pluripotency or STAP cells, by putting white blood cells under various stressors, including a low-pH, acidic solution for five minutes, and physical pressure. Vacanti said they tested five other conditions similar to those that happen in the human body during injury, and he thinks some combination of these factors will turn out to be most efficient at creating stem cells.
Although the research so far has been in mice, Vacanti said he recently created what appear to be STAP cells from human skin cells. That research needs to be replicated and peer reviewed before it is considered valid.
Rudolf Jaenisch, a stem cell biologist at the Whitehead Institute at the Massachusetts Institute of Technology, said he found the team's results quite surprising and cautions that more research is needed before the potential of this new approach can be understood. "I think it's a first step," he said. "Quite a lot of questions were unresolved."