Cambridge, MA, USA. A single pluripotent cell type powers the flatworm's extraordinary powers of regeneration, producing the diverse range of tissue types necessary to build a complete animal.

The discovery is useful to human regenerative medicine since there are human counterparts to most of the genes in the planarian genome. Further study should identify the molecular mechanisms that promote stem cell pluripotency, self-renewal, deployment, and regeneration.


Ever since animals, such as lizards and starfish, were observed regenerating missing body parts, people have wondered where the new tissues come from. Now we know that a single adult cell from one of the most impressive masters of regeneration in the animal kingdom – the planarian – is all it takes to build a completely functional new worm.



Peter W. Reddien, PhD, maintains a primary affiliation as a Member with the Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted.

He is also a Howard Hughes Medical Institute (HMMI) Early Career Scientist and an associate professor of biology at the Massachusetts Institute of Technology (MIT).The study yielded the first hard evidence that adult planarian flatworms (Schmidtea mediterranea) harbor pluripotent stem cells. Distributed throughout the worm body, the cells appear to have the same all-purpose qualities as embryonic stem cells. Such cells are essential for supplying the rapidly diversifying cells in a developing embryo, but usually disappear after the earliest stages of development. The planarian regenerative abilities are described in the journal Science.

Most advanced animals, including mammals, have a system of specialized stem cells. In humans, we have blood stem cells in our bone marrow that make blood and immune cells, skin stem cells that produce new layers of skin, and intestinal stem cells that continually renew our gut linings, to name just a few. In humans, only embryonic stem cells and germ cells are pluripotent — with the ability to create all cell types in the body.

However, this is the first time pluripotent stem cells have been identified in an adult animal, according to Peter Reddien, who led the study (cf. Sidebar). Scientists have long known about the planarians' remarkable capacity for regeneration, but the new discovery shows that "The feats of the individual cells are amazing," says Reddien. A new flatworm, complete with skin, nervous system, primitive eyes, gut, muscle, and internal organs, can emerge from a body fragment hundreds of times smaller than the match-head sized original.

Many animals, including people, continue to produce stem cells as adults, but precisely how the worms rebuild themselves cell-by-cell has been elusive. The central question to be answered is: where does all this material come from? Providing a cellular explanation for regeneration is one of the great problems biologists have faced.

Unlike embryonic stem cells, adult stem cells in most animals are limited to certain cell types. Hematopoietic stem cells in the bone marrow, for example, repopulate the various types of cells that make up the blood, whereas stem cells in the skin give rise to both skin and hair. Scientists have been unsure of the source for planarian regeneration. One all-purpose stem cell? Or several types of lineage-specific or tissue-specific adult stem cells working together?

In the planarian flatworm, certain dividing cells (called neoblasts) have long been identified as essential for the regeneration that repairs the worm's tissues. However, scientists could not determine whether neoblasts represent a mixture of specialized stem cells that each regenerates specific tissues or are themselves pluripotent and able to regenerate all tissues. "And that question is at the heart of understanding regeneration in these animals," says Reddien. "The reason it's never been possible to address this question is because we needed assays that allow us to ask what the regenerative potential of single cells is."

Using complementary methods, Dan Wagner, Irving Wang — two graduate students in the Reddien lab and co-first authors — and Reddien have demonstrated that adult planarians not only possess pluripotent stem cells — known as clonogenic neoblasts (cNeoblasts) — but that a single such cell is capable of regenerating an entire animal.

Wagner exposed planarians to a dose of ionizing radiation that destroyed the cells' ability to divide, except for rare, isolated cNeoblasts. Because regeneration was thought to depend on neoblasts, dividing cells that migrate to and proliferate at wounds and other sites in need of repair, the research team could use a radiation dose low enough to let some of these survive. The scientists then sorted through the cells to find neoblasts still capable of dividing.

By labeling cells for a gene expressed only in neoblasts, Wagner observed that these individual surviving cNeoblasts divided to form large colonies of cells. Wagner analyzed the colonies and found that they contained cells differentiating into neurons and intestinal cells, indicating broad developmental potential for the initiating cNeoblast. Furthermore, Wagner showed that small numbers of cNeoblasts were capable of restoring regenerative potential to entire animals.

The team then put the clonogenic neoblasts to the ultimate test: they transplanted a single cNeoblast into lethally irradiated host planarians from a different strain, which lacked their own neoblasts and the ability to regenerate. Because the donor cells were distinguishable from the host, the researchers demonstrated that the transplanted cNeoblast multiplied, differentiated, and ultimately replaced all the host's tissues. From a single transplanted cell, the host not only regained the ability to regenerate, but was also converted to the genetic identity of the donor strain.

What they observed, Reddien said, was "almost the type of event one might expect in a sci-fi movie." When a single neoblast is introduced into a planarian that cannot regenerate its own tissues, "eventually, it completely repopulates the animal with proliferating cells," Reddien explained. "Tissues of the host were slowly but surely replaced with descendant cells from the transplanted, donor cell. All the various parts of the body – kidney, gut, eyes, brain, skin, muscle –were regenerated. It all came from one original starting cell."

By the time the process is complete, every cell in the worm has assumed the genetic identity of the donor cell. The rescued worms appear normal in every way: "It can eat and grow. It can even reproduce through the asexual mode of reproduction," Reddien said. Because this work showed that cNeoblasts can differentiate into diverse tissue types and even replace all of the tissues in a host planarian, the researchers were able to conclude that cNeoblasts are pluripotent stem cells.

Further study of cNeoblasts could help researchers understand how stem cells can act to promote regeneration. "This is an animal that, through evolution, has already solved the regeneration problem," says Wagner. "We're studying planarians to see how their regeneration process works. And, one day, we'll examine what are the key differences between what's possible in this animal and what's possible in a mouse or a person."

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