Credit: Armin Hinterwirth

Salamanders are commonly used as regeneration models because they can grow new limbs after amputation. At the amputation site, a clump of undifferentiated progenitor cells called the blastema forms and then regenerates the missing tissues. A fully formed limb is comprised of multiple tissue types (including dermis, muscle, nerve and skeletal elements) that must coordinate in order for the limb to function properly. How the blastema is formed from these distinct tissue types and then goes on to regenerate them is not well understood, but new research from Elly Tanaka and colleagues (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany) is starting to clarify this complex process.

Previous work led many scientists to believe that blastema cells are pluripotent, or capable of differentiating into any type of cell. To establish this as fact, however, the different limb cell types would need to be tagged and then tracked during blastema formation and eventual limb regeneration. Tanaka's group developed a method of labeling different limb tissues in the axolotl (Ambystoma mexicanum, a member of the salamander group) with green fluorescent protein in order to monitor the tissues during limb regeneration. They found that each tissue type produced progenitor cells with restricted potential; cells kept a 'memory' of their tissue origin and were not pluripotent (Nature 460, 60–65; 2009). Dermis was the most plastic of the tissues tested and formed both cartilage and tendons, but not muscle, in addition to dermis. On the other hand, muscle and Schwann progenitor cells formed only muscle and Schwann cells, respectively, despite going through the blastema stage.

These results led to the conclusion that the blastema is a heterogeneous group of restricted progenitor cells rather than a homogeneous group of pluripotent cells. This means that limb regeneration in the axolotl occurs without complete de-differentiation of cells to a pluripotent state. In addition, the work suggests that, in terms of tissue specificity, blastema cells are similar to limb bud progenitors, the embryonic cells that go on to form limbs during vertebrate development. It isn't known yet how salamander cells at the site of amputation restart this normally embryonic program of tissue formation. Future research will examine gene activation and expression during regeneration in order to help clarify the molecular signals that control blastema cells and trigger the regeneration process. Tanaka believes that such research may lead to the possibility of limb regeneration in mammals.