Inducing Salamander-like Powers of Regeneration in Mammals

Salamanders, newts, and a few other types of amphibians replace lost or damaged limbs by triggering muscle cells to return to a more malleable state and then begin dividing, generating more muscle cells and eventually a new limb. Mammalian cells seem to have lost this power, preventing regeneration of most tissue.

Now a team of scientists at Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, led by Helen Blau, have shown that blocking two proteins in mouse muscle cells allows them to generate more muscle. The research was published today in Cell Stem Cell.

“Newts regenerate tissues very effectively,” said Blau, in a statement, from the university, describing her new research. “In contrast, mammals are pathetic. We can regenerate our livers, and that’s about it. Until now it’s been a mystery as to how they do it.”

To figure out why mammalian muscle cells can’t regenerate, Blau’s team looked for proteins known to block cell division, focusing specifically on those that are found in mammals and birds but not in amphibians capable of regeneration. They identified one candidate, called ARF. Blocking both this protein and a similar protein, Rb, identified in previous research, enabled cells isolated from mouse muscle to begin dividing. When transplanted back into mice, the engineered cells integrated with existing muscle fibers, but only if Rb was turned back on. The scientists haven’t yet shown that this muscle works properly.

Researchers ultimately hope to develop ways to regenerate tissue damaged via injury or disease. The ability to precisely re-grow cells in the pancreas or the heart, for example, could provide new therapies for diabetes or heart disease. The team now plans to examine whether the same approach will work in these types of cells.

However, the approach does present some risk. Blocking genes whose job is to prevent uncontrolled cell growth could lead to the development of tumors. According to a news story in Nature;

“There’s no question we’re playing with fire in knocking down tumour suppression,” says co-author Jason Pomerantz, a reconstructive surgeon currently at the University of California, San Francisco. The fear, he says, is that cells not protected by tumour suppressors can start to grow uncontrollably. But follow-up experiments suggested that temporarily suppressing the genes did not lead to tumours.

He and Blau believe that tissue could be treated as an explant – grown outside the body – and then implanted, or that drugs blocking the two genes could be injected directly into a spot at which regeneration is needed. “The heart is really where the bar would be set,” says Pomerantz. “There is no regeneration in the mammalian heart, and no bona fide stem cells that have been described that cause regeneration in adults.”