Salk Institute and Chinese researchers said they have created a new kind of stem cell, one that is more versatile than any other grown in the lab.

The new cell type, called an extended pluripotent stem cell, can give rise to every cell in the body, the scientists said. This quality is missing in both leading alternatives — embryonic stem cells that are harvested from an embryo and artificial embryonic stem cells called induced pluripotent stem cells.

The EPS cell not only can give rise to every cell in an embryo and adult organism, but also can make the placenta and other extra-embryonic tissues needed for the embryo to survive and grow. This ability enables the new type of stem cell to produce complete embryos and offspring, the scientists said.

And by injecting the cell into an tetraploid embryo, with double the chromosome count, the research team produced adult mice with every cell in their body originating from that single original EPS cell.


The process of growing whole animals is now being tested using the EPS cells without the tetraploid starter embryo, said study co-author and Salk Institute scientist Juan Carlos Izpisúa Belmonte.

EPS cells have been shown to integrate more effectively into chimeric animals as well. Chimeras are creatures with cells from two species, such as a combination of mice and pig — or human and animal.

“EPS cells will allow us to grow any tissue types and hold the potential to generate an entire embryo in a dish,” he said.

The study on this new stem cell was published April 6 in the journal Cell. It can be found at j.mp/extendedstem.


The scientists have created human EPS cells. But legal and ethical considerations prevent them from trying to turn those cells into babies.

Izpisúa Belmonte said the new stem cells will enable greater exploration of diseases from the very earliest stages of an organism’s development, including in the placenta.

In addition, he said, researchers will have an easier time making transgenic animal models for analysis of various diseases, as well as engineering chimeras with some human cells — for the purpose of cultivating organs that can be transplanted into people.

The study’s co-first authors were Jun Wu of the Salk Institute and Hongkui Deng, Yang Yang, Bei Liu, Jun Xu and Jinlin Wang, all from Peking University in Beijing.


Ethical issues

The EPS cells were made from two sources, from embryonic stem cells and from skin cells, or fibroblasts, by treating them with a chemical cocktail.

Induced pluripotent stem cells, invented in 2006, are generated from fibroblasts using a similar reprogramming process.

Use of induced pluripotent stem cells is regarded as morally acceptable by those who oppose use of human embryonic stem cells, because they can’t form an entire embryo.


The Roman Catholic church accepts work with induced pluripotent stem cells because they weren’t taken from an embryo, a process that kills the embryo. In addition, induced pluripotent stem cells can’t give rise to a complete embryo.

Rev. Tad Pacholczyk, a Catholic bioethicist and neuroscientist, said that the EPS cells represent a scientific advance and don’t pose a moral question, if not taken from embryos.

“In reviewing the paper, it seems these newly-derived stem cells are a more primitive and flexible cell source than traditional pluripotent stem cells,” said Pacholczyk, director of education at the National Catholic Bioethics Center in Philadelphia.

“While these cells do not appear to be embryos, they exhibit the remarkable property of being able to contribute to extra-embryonic lineages like those which give rise to the placenta, in addition to embryonic lineages,” said Pacholczyk, who holds a Ph.D. in neuroscience from Yale University, and also has worked as a molecular biologist at Massachusetts General Hospital/Harvard Medical School.


Evan Snyder, director for Stem Cells & Regenerative Medicine at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, also said there’s no ethical issue involved in using the new type of stem cell. They are a research tool to better understand embryonic development and treat disease.

“Although a study such as this may be misconstrued as posing an ethical conundrum (i.e., creating whole “designer” organisms from a single cell) or enabling new therapeutic interventions at very early stages of development), its real importance is first, in helping us better understand how human complexity emerges shortly after conception, and second, helping us understand how diseases, disorders, and syndromes in newborns and children arise,” Snyder said.

“Once the critical and vulnerable signaling pathways are understood, perhaps prenatal care can be improved to prevent problems and improve outcome.”

Better tool


That characteristic of creating every cell in the body, called totipotency, is normally found only at the very beginning of embryonic development. Embryonic stem cells are usually extracted too late, when the cells have already divided into the embryonic and extra-embryonic lineages.

Totipotent stem cells have been observed in the lab, but they lasted briefly, and didn’t yield stable totipotent cell lines. These totipotent-like cells can be stably cultured, retaining their ability to make embryonic and extra-embryonic tissues.

Salk Institute stem cell scientists Juan Carlos Izpisua Bemonte and Jun Wu (Salk Institute stem cell scientists Juan Carlos Izpisua Bemonte and Jun Wu)

The EPS cells “provide an unlimited cell resource and hold great potential for in vivo disease modeling, in vivo drug discovery, and in vivo tissue generation in the future,” the study stated. ”Finally, our study opens a path toward capturing stem cells with intra- and/or inter-species bi-potent chimeric competency from a variety of other mammalian species.”


Organs for transplant

The creation of chimeric mice is part of Izpisúa Belmonte’s longstanding goal of growing human organs in animals for transplant.

While mice are too small to grow organs for transplant, they serve as a model to understand how cells from a different species, can be grown in a host body. In this new study, the mice served as a model of how well the EPS cells can integrate.

Izpisúa Belmonte is now working to translate his research on chimeric mice to pigs, which are large enough to provide human organs. In January, a team he led reported on work with human-pig chimeras, which were not allowed to grow past the embryonic stage. They also created rat-mice chimeras.


The new study advances that work, said Wu, the other Salk Institute co-author.

“This particular (EPS) cell type coincidentally has a superior ability to generate chimeric embryos, either within the same species or across species,” Wu said. “It will be very interesting to test this cell type in the pig.”

Realizing a dream

Izpisúa Belmonte said being able to cure diseases and regenerate the body has been his passion ever since starting his scientific career. Some animals can regrow amputated body parts, but mammals cannot. Nobody knows why this is so.


“I have been approaching this question from different angles,” he said. “One of them is the use of stem cells. That is not the only one.”

The new research is important because it provides scientists with an even more flexible stem cell to probe questions of development and devise new therapies, he said. Making one cell that can give rise to all the cell types in an organism promises to be useful in regenerating body parts that are composed of many cell types.

“Having one specific cell that can do all the job -- that’s a dream come true, no?”

Izpisúa Belmonte said he expects to live long enough to see that dream turned into reality."I think yes. I’m very optimistic,” he said. “In the last few years, thanks to the people I have in the lab ... I feel we are learning things that in the end will have a practical outcome.”


The work was funded by a number of sources. They include: the National Key Research and Development Program of China; the National Natural Science Foundation of China; the Guangdong Innovative and Entrepreneurial Research Team Program; the Science and Technology Planning Project of Guangdong Province, China; the Science and Technology Program of Guangzhou, China; the Ministry of Education of China (111 Project); the BeiHao Stem Cell and Q9 Regenerative Medicine Translational Research Institute; the Joint Institute of Peking University Health Science Center; University of Michigan Health System; Peking-Tsinghua Center for Life Sciences; the National Science and Technology Support Project; the CAS Key Technology Talent Program; the G. Harold and Leila Y. Mathers Charitable Foundation; and The Moxie Foundation.

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UPDATES:

This story was originally published on April 15 at 9:20 p.m. It was updated on April 17 at 1:45 p.m. with additional information, including comments from several stem cell experts.