Learning from the Salamander
One of the dreams of medicine is to be able to replace a damaged limb with a healthy one, or, more generally, to improve the body’s ability to heal wounds. While humans cannot grow new limbs if one is lost, this amazing ability is found in some other animals, and it is hoped that by better understanding limb regeneration in such animals we will learn how to better heal ourselves.
This is why the salamander (Ambystoma mexicanum) a.k.a. the axolotl, an animal that can completely regrow a severed limb that is indistinguishable from the original, is widely studied. However, despite a large body of research over the years, how exactly the salamander accomplishes this remarkable feat has been unclear, and hotly debated.
That was, until recently. Research done by Elly Tanaka and her colleagues (at the Max Planck Institute of Molecular Cell Biology and Genetics and the Center for Regenerative Therapies at the University of Technology, both in Dresden, Germany) has revealed that the mechanism by which salamanders regrow lost legs is actually quite different from what it was long believed to be.
When a salamander has a limb severed, the resultant stub (called a “limb bud”) undergoes a well-defined process in regrowing the lost appendage. First on the scene is the epidermis (the outer layer of skin), which grows and expands to cover the wound, closing it within 24 hours after the injury. This layer thickens and then cells from the immune system (macrophages and neutrophils) arrive to clean up the wound, breaking down the injured tissues, cells, and proteins underneath the epidermis.
It is at this point in the regeneration process that stem cells take center stage. As the limb bud becomes home to an increasing number of stem cells, it is re-named the “blastema.” For a long time scientists knew that there are stem cells in the blastema, but the exact type of stem cells, where they come from, and how exactly they contribute to regenerating the limb in the blastema were fairly mysterious.
Stem cells are special cells because they can not only renew themselves continually (always creating another stem cell to replace the previous one), but can also turn into other, more mature types of cells. Since the mid-1990s, researchers thought that the blastema contained a homogenous (where all cells are identical) group of pluripotent stem cells. (“Pluripotent” means that each individual stem cell would be capable of becoming any type of cell.) The theory went like this: Mature cells in the tissue surrounding the blastema were (somehow) stimulated by the epidermis and nearby cells to become pluripotent stem cells in order to recreate the new limb.
This model was challenged by recent experiments done by Elly Tanaka’s group. Tanaka and colleagues revealed that the limb regeneration process in salamanders is actually accomplished by a heterogeneous (mixed) population of multiple different types of stem cells that can actually only become one or two different types of mature cell types (making these stem cells unipotent or multipotent at best, but far from pluripotent).
In their efforts to resolve the long-standing debate, Tanaka and her researchers developed a way to track where each different tissue type was during limb regeneration. What they found was that the blastema actually contains different precursors for all the different tissue types that are found in the complete limb. Specifically, the blastema contained precursor cells for all the mature tissue types, but each precursor could only become one or two specific adult tissue types. So it appears that, rather than the mass of magically-coordinated pluripotent cells once believed to be present, several different types of rather limited stem cells may work together to regenerate the entire limb.
In fact, only one of the tissue types that Tanaka’s group appeared capable of becoming more than one type of mature tissue, and this was the dermis, an inner skin layer. The dermis progenitors could turn into either dermis or cartilage, but not other tissue types investigated. In developing salamander embryos, dermis and cartilage actually share a common tissue origin (specifically, the mesoderm), which helps explain why the dermis-layer cells could become either dermis or cartilage.
Similar to salamanders, it’s been found that some frogs (of the genus Xenopus) also regrow their limbs using a blastema that has a heterogenous mix of progenitor stem cells. It’s still unclear whether other animals, on the other hand, may regenerate themselves by reverting mature cells to a pluripotent state (as was long thought to be done by salamanders), or perhaps by changing one mature cell directly into another mature type.
While a universal regeneration mechanism between different animals known to be able to regenerate their limbs or parts of their limbs remains unclear, what is clear is that such research could be quite useful for future regenerative medicine research in humans. The salamander studies indicate that we may not need pluripotent cells for complex tissue regeneration, but instead could use multiple different stem cells with much more limited potentials. As a variety of different, limited stem cells can be fairly easily harvested from an adult human patient (such as hematopoietic and mesenchymal stem cells), this presents a vision of human tissue regeneration. While this does not necessarily make the process immediately feasible, it may help give researchers a more focused direction for future studies.
For more on limb regeneration in the salamander, see Teisha Rowland’s “Limb Regeneration May Require Less Potent Stem Cells Than Previously Thought” or Elly Tanaka’s article on Cells keep a memory of their tissue of origin during axolotl limb regeneration, or, for a visual explanation of terms used, see All Things Stem Cell’s Visual Stem Cell Glossary.
Biology Bytes author Teisha Rowland is a science writer, blogger at All Things Stem Cell, and graduate student in molecular, cellular, and developmental biology at UCSB, where she studies stem cells. Send any ideas for future columns to her at email@example.com.