Defying accepted notions, cells in newly growing salamander legs seem to remember their origin
Cut off a salamander's leg, and it grows anew. The ability of amphibians to regenerate legs and tails has inspired researchers hoping to regrow human limbs and organs. The assumption has been that differentiated salamander cells somehow retain a flexibility that is lost in mammalian counterparts but that could, perhaps, be restored.
The healing starts with what looks to be an early embryo. The solid half-ball of cells that forms at the amputation site is termed a blastema, and eventually it generates the bone, muscle and nerves that a new limb needs. The cells in a blastema all look similar, and conventional wisdom held that the cells were indeed homogenous, arising from specialized cells that dedifferentiated. New work shows instead that salamander cells are like those of mammals, capable of regrowing into only the original tissue type.
Elly Tanaka, now at the Center of Regenerative Therapies Dresden, in Germany, and colleagues at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden found that although these cells may lose their specialized markers and appearance, they still retain a memory of the tissue they came from1.
Tanaka used transgenic salamanders (Ambystoma mexicanum) to reassess whether cells in the blastema dedifferentiated to a pluripotent state in which they would be capable of becoming any tissue. Researchers labelled each major limb tissue with green fluorescent protein in two ways: by grafting green embryonic tissue destined to become, say, muscle tissue into a nongreen host embryo or by directly grafting developed limb tissue into an unlabelled host. This tissue could then be followed as amputated limbs grew back.
Time and again, in juveniles and adults, the researchers saw similar results: Cells that arose from muscle did not make skin or cartilage but only muscle, nor did the so-called Schwann cells that cover neurons in a myelin sheath become cartilage. What's more, the cells also seemed to know whether they belonged to the upper or lower parts of a limb.
These results imply that the blastema is a mixture of cells, with each cell returning to its original tissue type. "Cells don't have to revert to a pluripotent state in order to regenerate a complex, multi-tissue structure," explains Tanaka. "The progenitor cells that regenerate the limb are like those we expect to find in the developing limb bud."
However, even if the cells do not revert back to a pluripotent state, they do seem to behave like their counterparts in embryonic tissues. Tanaka is now working to identify the cascades of gene expression that are activated for each lineage after limb injury. She is also working on how different tissue-specific stem cells turn on a gene program that tells them whether they are in the, say, upper or lower arm or hand.
Lessons in regeneration will still be coming from amphibians, it seems — just not quite the lessons we were expecting.
Kragl, M. et al. Cells keep a memory of their tissue of origin during axolotl limb regeneration. Nature 460, 60–65 (2009).
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Baker, M. Regenerating limb tissue may not dedifferentiate. Nat Rep Stem Cells (2009). https://doi.org/10.1038/stemcells.2009.96