A little acid or a tight squeeze can turn a cell stemlike

Stresses send mouse cells into primordial state capable of making any tissue

10:26am, January 29, 2014

TAILOR MADE  Stress can reprogram cells to become STAP cells (green), a new variety of stem cell that can become any type of cell. Researchers used these cells to grow an entire mouse fetus.  

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Editor's Note: The research described in this article is the subject of a reported February 2014 investigation by RIKEN. Read more about the concerns about the findings and some researchers' unsuccessful attempts to replicate the work. The papers were retracted in July 2014.

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Creating stem cells may be as simple as dunking cells briefly into a mild acid bath.

Doing so with mouse cells turned them into ultraflexible ones that can grow into any type of body tissue, researchers report in two papers in the Jan. 30 Nature. Other types of stress, such as squeezing cells through narrow glass tubes, can also reprogram cells, Haruko Obokata of the RIKEN Center for Developmental Biology in Kobe, Japan, and Harvard Medical School and her colleagues discovered.

The easy technique, if it works on human cells, could provide replacement cells for diseased body parts, foster a better understanding of a person’s disease risks and drug sensitivities, and maybe even serve as a fertility treatment.

The method has floored other researchers, who thought that creating stem cells required more-complex operations: extracting cells from embryos, transferring the nucleus of an adult cell to an egg cell, or using viruses or other means to introduce factors into the cell that reprogram it to be embryonic-like.

“It’s fascinating. It’s perplexing. It’s potentially profound, but leaves lots of reasons to scratch my head,” says George Daley, the director of stem cell transplantation at Boston Children’s Hospital and Harvard Medical School. “It’s begging to be replicated,” he says, adding that his lab will attempt to do just that.

In the new study, about 7 to 9 percent of cells from newborn mice survive the acid treatment and take just a week to form primordial cells, dubbed STAP cells for stimulus-triggered acquisition of pluripotency. Pluripotent cells are capable of developing into cells from any tissue. Both embryonic stem cells and reprogrammed cells known as induced pluripotent stem cells, or iPS cells, are pluripotent.

STAP cells may be even more flexible, Obokata says. When injected into mouse embryos, STAP cells not only incorporate into any body tissue but they can also form parts of the placenta. That’s a feat other pluripotent cells generally can’t accomplish, and it may indicate that STAP cells are totipotent, or capable of forming a complete organism. Growing STAP cells under different conditions in lab dishes also produced stem cells that could grow into fetal tissues. Slightly different conditions yielded cells resembling placenta precursor cells called trophoblasts.  

Obokata and her colleagues transformed blood, skin, brain, muscle, fat, bone marrow, lung and liver cells from newborn mice into STAP cells. The technique worked, but not as well, on cells from older mice, she says. The researchers have begun testing the acid treatment on human cells.

The new reprogramming method’s simplicity has taken other researchers aback.

Dieter Egli, a stem cell researcher at the New York Stem Cell Foundation, is skeptical of the findings. “If I were to describe this over a coffee break to one of my colleagues, they’d say, ‘you must be kidding,’” he says. He knows of no mechanism that could explain how mild acid or squeezing changes a cell’s fate so dramatically and consistently in one direction. Egli wonders why, for instance, blood cells became stem cells instead of transforming into muscle or any other type of cell.

Cells experience stress all the time, Egli points out, from sources such as low oxygen, high or low temperatures, mechanical stress from exercise and chemical stress from inflammation. If simple acid or mechanical stress causes cells to revert to an early developmental state, he says, “it’s hard to imagine how our bodies would maintain integrity over a lifetime.”

But Qi-Long Ying, a stem cell biologist at the University of Southern California’s Keck School of Medicine in Los Angeles, speculates that the body produces inhibitory factors that prevent stress from reprogramming cells. Without those inhibitions, lab-grown cells can regress to an immature state. Understanding how stress reverts mouse cells to the anything-goes state may teach researchers more about cancer, another condition in which cells have no particular identity and grow rapidly. He worries that cells reprogrammed by stress might be more susceptible to becoming cancerous.

On the road to using STAP cells in individualized medicine, ethical barriers may also pop up. Because STAP cells may be totipotent, James Byrne, a stem cell researcher at UCLA, worries that the new technology may raise old specters of human cloning. Debates over the ethics of embryonic stem cell research were largely pushed to the side when researchers learned how to reprogram adult cells into iPS cells. Because iPS cells usually don't form placenta, they probably would not grow into a fetus if directly transplanted into a uterus. But acid-reprogrammed cells potentially could grow into a fetus, placenta and all. If that’s true, the cells might be used to treat infertility by creating an embryo from an adult’s cells, Byrne says.

The new method is just one of many ways to create stem cells, says Louise Laurent, a stem cell biologist at the University of California, San Diego and the Sanford Consortium for Regenerative Medicine. If stress reprograms human cells as quickly and efficiently as it does mouse cells, it may have advantages over older techniques. Ultimately, researchers conducting clinical trials will choose the most stable cells that faithfully reproduce tissues of interest, Laurent says.

Much research is needed to show whether STAP cells can compete with other types of stem cells, she says. Regardless of the final outcome, she says, “these papers will inspire people to explore less traditional ways of changing a cell’s fate.”

BACK TO BASICS  After half an hour in mild acid, a mouse’s white blood cells can convert to a new type of stem cell known as STAP cells. Cells undergoing conversion turn on a gene called Oct4 (green), which helps in reprogramming the cell to a primordial state. The STAP cells eventually developed into a mouse embryo with a beating heart. All of the organism’s cells grew from the new type of stem cell, which can also make part of the placenta (not shown).

Credit: H. Obokata

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