Disabling an evolutionary backup plan for protecting against cancer could be part of a future means to regrow lost limbs or regenerate damaged organs.
A protein called ARF, which acts as a fail-safe mechanism to protect against cancer, also prevents regeneration in mammals, a study published August 6 in Cell Stem Cell suggests. ARF backs up Rb, an important anticancer protein, by limiting the ability of mature cells to divide and replicate. But researchers in California have discovered that blocking ARF and Rb allowed mature muscle cells taken from mice to proliferate, something the cells normally cannot do.
The discovery is an important step in learning why mammals, including people, can’t regrow or replace lost limbs and organs the way animals such as salamanders and zebrafish can. Such work may one day lead to new treatments for injuries.
Scientists have known for many years that some animals, including some fish and amphibians, can regenerate organs and limbs, but mammals can’t. Therefore, at some point in evolution, mammals must have acquired proteins that halt regeneration, reasoned Stanford University researchers led by Helen Blau and Jason Pomerantz, who is now a professor at the University of California, San Francisco.
Other studies had shown that inactivating Rb in salamanders could kick off the regeneration process. But in mammalian cells, getting rid of Rb isn’t enough to spur growth, Blau says. That’s because mammal cells have ARF to take over if Rb goes down. Newts, salamanders and zebrafish don’t have the ARF backup system.
“We put two and two together” and deciphered that Rb and ARF could be working together to put the brakes on regeneration, Pomerantz says.
The team tested the idea by taking muscle cells from mice and temporarily depleting the Rb and ARF inside. Cells that lacked the two cancer guards were able to replicate themselves, while normal muscle cells could not. Further experiments showed that the regenerated cells could incorporate into muscles in the mice. That finding is important because it could mean that if heart cells could be coaxed into regenerating, they might help heal injuries caused by heart attacks.
Making the protein inactivation temporary was also key. If researchers permanently removed the proteins from cells, the cells would form tumors when transplanted into mice.
But the scientists caution that real regeneration of entire limbs or organs is still a long way off. “Growing a whole limb, that’s hugely complicated,” says Blau.
The researchers also have not yet shown that inactivating Rb and ARF can lead to true regeneration — growing an entirely new tissue, says Kenneth Poss, a developmental biologist and Howard Hughes Medical Institute investigator at Duke University Medical Center in Durham, N.C.
“Regeneration is an extremely complex process that I don’t think will boil down to just one cellular event or one molecular event,” he says. In addition to being able to replicate, cells probably also need some guidance about how to reform limbs and tissues. Whether such a guidance system is at work in mammals is unknown.
“I think it will be exciting to see whether they can use these manipulations to enhance regeneration” in mammals, Poss says.
