When a salamander is faced with a predator, it may simply cause its tail to fall off, which flops around distracting the predator while the salamander scampers away. It will grow a new tail. It can also grow an entire new limb if it needs one. The salamander is not unique in its capability to grow new appendages. Tadpoles, newts and other amphibian species can regenerate limbs and fish caudal fins can regenerate after amputation(ref). I thought I would look a bit into how these animals go about doing that and the implications for human limb regeneration.
This recent citation outlines the general process. “When a salamander loses an appendage, such as a limb, a remarkable series of events unfolds: a clump of cells forms at the site of the injury, and this deceptively simple structure, known as a blastema, regenerates the missing body parts. Skin, muscle, bone, blood vessels and neurons all arise from this collection of nondescript cells through patterning and self-assembly.” According to another study report “Axolotl (salamander) limb regeneration is considered by many to be divided in two main phases , , . The first phase is referred to as the preparation phase and begins immediately following amputation with the formation of a wound epithelium (WE) over the amputation plane. Cellular dedifferentiation and migration, which will eventually lead to the formation of a regeneration blastema, also take place in this phase. In the second phase of limb regeneration, referred to as the redevelopment phase, blastema cells stop proliferating and start to redifferentiate to regenerate the lost part , (ref).”
Another recent publication looks at the cells in the blastema. “During limb regeneration adult tissue is converted into a zone of undifferentiated progenitors called the blastema that reforms the diverse tissues of the limb.” – “Surprisingly, we find that each tissue produces progenitor cells with restricted potential. Therefore, the blastema is a heterogeneous collection of restricted progenitor cells. On the basis of these findings, we further demonstrate that positional identity is a cell-type-specific property of blastema cells, in which cartilage-derived blastema cells harbour positional identity but Schwann-derived cells do not. Our results show that the complex phenomenon of limb regeneration can be achieved without complete dedifferentiation to a pluripotent state, a conclusion with important implications for regenerative medicine(ref).” This work relates to the salamander Ambystoma mexicanum (the axolotl). As I understand it, this says that the blastema consists of progenitor cells for the various tissues that will be in the final limb but not fully pluripotent stem cells that can differentiate into anything.
But how is the blastema formed? It appears that de-differentiation of stump tissue is involved(ref). In other words, if you tear off a salamander’s leg, cells in the tissue left in the stump responds by de-differentiating from their initially highly specific types into progenitor cells in the blastema.
Put yet another way “Epimorphic regeneration following limb amputation involves wound healing, followed shortly by a phase of dedifferentiation that leads to the formation of a regeneration blastema. Up to the point of blastema formation, dedifferentiation is guided by unique regenerative pathways, but the overall developmental controls underlying limb formation from the blastema generally recapitulate those of embryonic limb development(ref).” Again it is a two-phase process, first of de-differentiation to form the blastema, and then of limb formation which is similar to that of embryonic limb development. It works that way in salamanders but generally not in mammals who do not form a blastema when a limb is lost. “Epimorphic regeneration usually produces an exact replica of the structure that was lost, but in mammalian tissue regeneration the form of the regenerate is largely determined by the mechanical environment acting on the regenerating tissue, and it is normally an imperfect replica of the original(ref).”
Nontheless, research on salamander limb regeneration may turn out to be quite relevant to humans since some of the underlying mechanisms of tissue regeneration may be similar. Mammals have a very limited capability to regenerate appendages compared to salamanders but still can do so to a limited extent. For example, mice and men can regenerate ends of fingertips. “–genetic studies on mouse digit tip regeneration have identified signaling pathways required for the regeneration response that parallel those known to be important for regeneration in lower vertebrates. In addition, recent studies establish that digit tip regeneration involves the formation of a blastema that shares similarities with the amphibian blastema, thus establishing a conceptual bridge between clinical application and basic research in regeneration. In this review we discuss how the study of endogenous regenerating mammalian systems is enhancing our understanding of regenerative mechanisms and helping to shed light on the development of therapeutic strategies in regenerative medicine(ref).”
The hope for limb regeneration is worthy of science fiction. After amputating your brother’s arm that was completely crushed in an auto accident, the doctor tells him “We will get your body to form a blastema that will turn into a new new arm during your visit next week. But then you will need patience. It will take several years before the arm grows to full size and links completely up to your body nerve and vascular systems. During that time the new arm will most likely be awkward.”
Researchers are developing insights that may lead to realization of that hope. For example, de-differentiation of stump tissue in salamanders may result from the activation of skeletal muscle multipotent satellite cells(ref). “We describe a multipotent Pax7+ satellite cell population located within the skeletal muscle of the salamander limb. We demonstrate that skeletal muscle dedifferentiation involves satellite cell activation and that these cells can contribute to new limb tissues. Activation of salamander satellite cells occurs in an analogous manner to how the mammalian myofiber mobilizes stem cells during skeletal muscle tissue repair. Thus, limb regeneration and mammalian tissue repair share common cellular and molecular programs. Our findings also identify satellite cells as potential targets in promoting mammalian blastema formation(ref).”
Another stream of similarity between human wound healing and salamander limb regeneration involves TGFÎ², transforming growth factor beta. “Multiple authors have recently highlighted the similarities between the early phases of mammalian wound healing and urodele (amphibians of the order Caudata, including salamanders and newts) limb regeneration. In mammals, one very important family of growth factors implicated in the control of almost all aspects of wound healing is the transforming growth factor-beta family (TGF-Î²).” – “Our results also demonstrate the presence of multiple components of the TGF-Î² signaling machinery in axolotl (salamander) cells. By using a specific pharmacological inhibitor of TGF-Î² type I receptor, SB-431542, we show that TGF-Î² signaling is required for axolotl limb regeneration(ref).”