Can Humans Harness the Limb Regeneration Abilities of Salamanders?

The remarkable adaptations of salamanders provide a glimpse into the future of regenerative medicine and its application to humans.

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Limb regeneration has long been a subject of fascination in biology. While this remarkable ability is widespread in the animal kingdom, humans have traditionally been thought to lack this regenerative power. Unlike certain animals, such as salamanders—who can regenerate their limbs, bones, and other body parts after injury—humans can only regenerate tissues like the epidermis (the outermost layer of the skin) and some organs, like the liver, after injury. However, recent scientific breakthroughs have shed light on the possibility of limb regeneration in humans, offering hope for the future of regenerative medicine.

The limb regeneration process is well-documented in salamanders, such as axolotls, which hatch in ponds alongside other species that feed on them during birth. This behavior may explain why they evolved to have the ability to regenerate missing limbs and gills. In axolotls, the process that allows for the regeneration of an entire limb involves complex teamwork between the limb’s surviving cells. When a limb is lost from injury, a clot of blood cells rapidly stops bleeding at the cut site. After this, a layer of cells quickly covers the amputation site, forming a wound epidermis, the first protective layer of skin. During the next few days, the wounded epidermis cells grow and divide rapidly, as do the cells underneath the epidermis, forming a cone-shaped structure known as a blastema. The cells that compose the blastema are thought to be bone, cartilage, muscle, and other cells that dedifferentiate (lose their identity), only to re-form into various cell types depending on the specific needs of the regenerating tissue. This multipotency—the ability to develop into more than one cell type—is a critical factor in tissue regeneration and is a feature that sets them apart from typical, fully-differentiated cells. These dedifferentiated blastema cells then grow and multiply, eventually regaining their identity as fully-developed bone, skin, or any needed cell, depending on the injury. As the blastema cells divide, the growing structure of the blastema flattens to resemble a perfect copy of the lost limb, down to the very nerves and blood vessels that connect it to the rest of the body—a process known as angiogenesis and neurogenesis. While these processes are not part of the blastema formation, they are vital components of tissue regeneration. The interaction and coordination of these processes with blastema formation and differentiation ensure the functional recovery of the regenerating tissue by providing it with a blood supply and neural connections.

Scientists have been studying axolotls for more than 200 years to understand the mechanisms of limb regeneration in hopes of inducing more extensive regeneration in humans. Scientists have long believed two things must be present in an affected area to induce mammalian regeneration. The first is growth factors, which are molecules that can stimulate cells to regrow and reconstruct parts of the body. The human body naturally produces a variety of growth factors that regulate processes like tissue repair and regeneration. One of the most important growth factors is the Platelet-Derived Growth Factor (PDGF), produced by blood platelets and other cells that play a key role in stimulating cell expansion in the early stages of wound healing. Another significant growth factor is the Vascular Endothelial Growth Factor (VEGF), which is involved in angiogenesis, the formation of new blood vessels. VEGF helps supply oxygen and nutrients to regenerating tissue.

In therapeutic contexts, exogenous (externally supplied) growth factors can be used to promote regeneration. For example, in regenerative medicine and tissue engineering, scientists can introduce specific growth factors into the site of injury or tissue damage to stimulate the regeneration process. This approach enhances the body’s natural regenerative capacity in cases where it may be insufficient. In bone regeneration, bone morphogenetic proteins (BMPs) are used to stimulate the differentiation of mesenchymal stem cells into bone-forming cells. 

Growth factors can also be used in conjunction with stem cell-based therapies. Stem cells have the potential to differentiate into various cell types, and growth factors are often used to guide and accelerate this differentiation process. For instance, the Center for Regenerative Medicine (CRM) harnesses the regenerative power of a patient’s stem cells from their bone marrow to help them rebuild or regenerate muscle, vascular, and nerve tissues, striving for complete recovery—and ultimately, limb recovery. Shortly after the injury, bone marrow mononuclear cells (BM-MNCs) extracted from the patient’s bone marrow can be used to help the body fight adverse inflammation and equip neighboring cells with the tools they need to heal and grow. This treatment has already been proven effective in translational pre-clinical studies and recently received FDA approval to begin its first treatments in patients. The Armed Forces Institute for Regenerative Medicine, which envisions a potentially necessary therapy for injured soldiers, has committed to funding half the cost of the first clinical trial to establish feasibility and safety studies in humans. 

The second factor believed to be necessary for mammalian regeneration is nerves. As mentioned before, nerves play an important role in the functioning of generated tissues and bones, as they link cells to the body and allow them to function. In peripheral nerve injuries, accidents, or induced injuries, scientists have used nerve grafts to bridge the gap between severed nerve ends. These grafts come in two forms: autografts (nerves taken from the patient’s body) or allografts (nerves from a donor), and both can be transplanted to facilitate nerve regeneration. However, scientists are researching ways to optimize the success of these grafts and improve outcomes, as the current procedures are challenging. Additionally, scientists are developing bioengineered nerve conduits that can guide nerve regeneration. These conduits may be made from biocompatible (not harmful) tissue materials and could be designed to release growth factors or other signaling molecules to promote the growth of nerve fibers. However, key precautions must be taken in this process. Firstly, selecting the right materials and ensuring they remain biocompatible over time can be a complex task, as the materials must not trigger an immune response or cause tissue rejection. Additionally, other factors—infection risk, inflammatory responses, and integration with surrounding tissues—make this process difficult and necessitate further research before its application.

While the prospect of limb regeneration in humans is promising, there are still significant challenges to overcome and ethical protocols to outline. Factors such as informed consent, safety, prevention of reproductive cloning, environmental impact, patient privacy, and much more need to be addressed before considering methods of stem cell transplantation. These issues require transparent guidelines and regulatory oversight, but with continuous technological advancements in other stem cell therapies, the dream of limb regeneration in humans is no longer confined to the realm of science fiction. Recent advances in tissue engineering and regenerative medicine techniques have brought us closer to the possibility of regenerating lost limbs due to injuries. The potential for human limb regeneration offers hope for those who have suffered from amputations and traumatic injuries. Thus, the remarkable adaptations of salamanders provide a glimpse into the future of regenerative medicine and its application to humans.