Though often no bigger than an apple seed, planaria are the envy of the animal kingdom. Cut them into a dozen pieces, and each piece will regrow into a full new worm—a remarkable feat of regeneration beyond the ability of most other animals. Now, researchers have pinpointed the cell—and a key protein—that kick-starts this process.
The discovery “is a major breakthrough in the field,” says Ricardo Zayas, a developmental biologist at San Diego State University in California who was not involved with the work.
Researchers have known for decades that a group of unspecialized stem cells called neoblasts help planaria regenerate. But they’ve failed to figure out exactly which type of neoblast works this magic. So Alejandro Sánchez Alvarado, a developmental biologist at the Stowers Institute for Medical Research in Kansas City, Missouri, tapped new techniques for isolating single cells and characterizing their gene activity. That quest led him and his colleagues to 12 possible candidate cell types for a master regenerative cell, of which one had an unusual protein on its surface that resembles a class of cell surface molecules, called tetraspanin, that has been implicated in human cancer—these proteins help tumor cells spread throughout the body.
By making a fluorescent tag that homed in on the worm’s tetraspanin, the researchers were able to isolate just this one cell type, dubbed neoblast subtype No. 2 (Nb2), for further testing. When the team cut planaria and followed wound recovery, the Nb2 cells increased rapidly in number, the team reports today in Cell. This army of cells healed the wound caused by the cut. In another experiment, a single injected Nb2 cell was able to multiply and diversify to rescue planaria that had been given a lethal dose of radiation.
Nb2 cells are a special type of stem cell. In other organisms, only the very first cells of the developing embryo (known as totipotent cells) are able to form all the body’s tissues. Later in life, humans’ and other animals’ stem cells can only make a limited selection of cell types (known as pluripotency) or a single type. “Somehow planaria have retained cells” that can become any type they want, Sánchez Alvarado explains.
He and his colleagues discovered that Nb2 cells are always present throughout the planaria body. But they increase gene activity to make tetraspanin only in wounded individuals. And the protein seems key: When the researchers put neoblasts that didn’t make tetraspanin in dying planaria, the planaria did not recover.
It’s not yet clear why this protein is so important, but it seems to be involved in cell-to-cell communication. Its role in spreading cancer cells suggests it may also help cells get to parts of the planaria that need fixing.
With the antibody that can tag and isolate Nb2 cells, Sánchez Alvarado and others can now look in more detail at how the tetraspanin works and what turns on its production in these cells. Others, too, are making progress in getting at the molecular details of regeneration. Last month, Peter Reddien, a developmental biologist at the Massachusetts Institute of Technology in Cambridge reported in Science that his team had tracked gene activity in every cell as the planaria regenerated. Another group did a similar study.
Reddien is eager to go back to his study to see whether his group’s comprehensive look at all cells also identifies an Nb2 cell type. “It’s too early to say how those findings will translate into therapies,” to restore body parts in humans, Reddien says. “But discovering the mechanisms that allow natural regeneration to occur is a good start.”