By tracking individual cells in genetically modified salamanders, researchers have found an unexpected explanation for their seemingly magical ability to regrow lost limbs.
Rather than having their cellular clocks fully reset and reverting to an embryonic state, cells in the salamanders’ stumps became slightly less mature versions of the cells they’d been before. The findings could inspire research into human tissue regeneration.
“The cells don’t have to step as far back as we thought they had to, in order to regenerate a complicated thing like a limb,” said study co-author Elly Tanaka, a Max Planck Institute cell biologist. “There’s a higher chance that human or mammalian cells can be induced into doing the same thing.”
Thinkers from Aristotle to Voltaire and Charles Darwin have been fascinated by salamander regeneration, though they barely understood it. (Aristotle even confused salamanders with snakes, attributing to the latter the power of growing new eyes.) But only in the last few decades have scientists been able to study the phenomenon at high resolution.
They found that salamander regeneration begins when a clump of cells called a blastema forms at the tip of a lost limb. From the blastema come skin, muscle, bone, blood vessels and neurons, ultimately growing into a limb virtually identical to the old one.
Researchers, many of whom hoped their findings could someday be used to heal people, hypothesized that as cells joined blastemas, they “de-differentiated” and became pluripotent — able to become any type of tissue. Embryonic stem cells are also pluripotent, as are cells that have been genetically reprogrammed through a process called induced pluripotency.
Such cells have raised hopes of replacing lost or diseased tissue. They’re also difficult to control and prone to turning cancerous. These problems may well be the inevitable growing pains of early-stage research, but could also represent more fundamental limits in cellular plasticity.
If Tanaka’s right that blastema cells don’t become pluripotent, then the findings raise another possibility — not just for salamanders, but for people. Rather than pushing cellular limits, perhaps researchers could work within nature’s parameters.
“People working on stem cells are trying to de-differentiate cells in an artifical fashion,” said Alejandro Sánchez Alvarado, a Howard Hughes Medical Institute stem cell biologist who was not involved in the study. “It will be very important for the regenerative-medicine community to take stock of what’s going on in the salamander, because they’ve been doing it for 360 million years, and found a natural way to de-differentiate their tissues.”
Having first added a gene that makes a fluorescent protein into the genomes of axolotl salamanders, Tanaka’s team removed from their eggs the cells that would eventually become legs. They fused the cells into new eggs; when these matured into adult salamanders, cells in their legs glowed under a microscope.
After the researchers amputated their salamanders’ legs, the legs regrew. Cells in the new legs also contained the fluorescent protein and glowed under a microscope, so the scientists could watch blastemas form and legs regrow in cell-by-cell detail.
Contrary to expectation, skin cells that joined the blastema later divided into skin cells. Muscle became muscle. Cartilage became cartilage. Only cells from just beneath the skin could become more than one cell type.