Spinal cord injuries and pathologies are incredibly debilitating diagnoses which often have bleak outcomes and significant impacts on patients’ quality of life. The World Health Organization estimates that about 250,000–500,000 people are afflicted by these injuries every year, but — according to the American Spinal Injury Association — current treatments only lead to functional recovery in about 2.1 percent of cases. In response to this clear lack of success with current treatments, researchers are thinking outside the box and turning towards amphibians for answers.
The astounding regenerative potential of amphibian species has captivated researchers since it was first characterized by Lazzaro Spallanzani in the early 1700s. Salamanders, especially those belonging to the Ambystoma family, have been at the forefront of this research due to their exceptional regenerative capabilities. These animals are able to entirely regenerate complex, multi-tissue structures like their limbs and spinal cord segments. Given that these tetrapods are distantly related to humans, many believe that the same regenerative potential could be unlocked in human patients.
These animals are able to entirely regenerate complex, multi-tissue structures like their limbs and spinal cord segments.
Despite decades of study, the exact mechanisms by which salamanders regenerate has long eluded researchers. Fortunately, recent advancements in genetics, transcriptomics, and fluorescence imaging have led to rapid growth in our understanding of the cellular processes and signaling pathways unique to amphibian injury responses. We now know that there are three crucial components of the amphibian regenerative response which mammals lack.
The first is populations of tissue-specific progenitor cells. These adult stem cells normally lie dormant within tissues, but, in response to injury, they begin to proliferate and replace lost cells. For example, muscle tissues in adult axolotl salamanders contain dispersed populations of Pax7+ myocytes. When regenerative programs are initiated in response to a critical injury, these muscle progenitor cells begin rapidly dividing. Numerous studies have used lineage tracing, a technique which labels a given cell and all of its progeny, to confirm that these cells rapidly proliferate and differentiate after injury, eventually forming all of the muscle cells in a regenerated structure.
Amphibians also differ from mammals with regard to how their immune system responds to injury. In humans, when the spinal cord suffers acute damage, there is a massive influx of immune cells and inflammatory signals. These immune cells begin eating up cellular debris and releasing cytokines, which are signaling proteins that trigger and exacerbate the inflammatory response. This inflammation attracts astrocytes, a form of glial cell, which accumulate within the wound site and produce a physical barrier referred to as a “glial scar.” This combination of inhibitory signaling with a physical barrier makes it impossible for axon fibers to traverse the site of injury. Without axonal outgrowth, neurons cannot re-establish the connections needed to produce functional recovery. In contrast, when the spinal cord of an axolotl is injured, immune cells still respond, but instead of promoting inflammation they secrete pro-proliferative signals and clear up debris to facilitate the replacement of damaged cells.
The third essential component of the salamander injury response is the activation of neurotrophic signaling pathways, which promote new growth and survival of neurons. For nearly a century, the identities of the neurotrophic factors unique to amphibian regenerative responses have eluded discovery. Luckily, considerable progress has been made in this respect, and several signaling molecules have received strong support suggesting their importance for facilitating neuron growth and recovery after injury.
Armed with this new knowledge, researchers have begun to develop novel treatment regimens which attempt to mimic the pro-regenerative conditions seen in amphibians.
Armed with this new knowledge, researchers have begun to develop novel treatment regimens which attempt to mimic the pro-regenerative conditions seen in amphibians. One study conducted in primates at the University of California, San Diego found that functional recovery after spinal cord injury could be achieved if: (1) the glial scar was removed; (2) neural stem cells were injected; and (3) a “cocktail” of neurotrophic growth factors was added. Studies like these provided the first evidence that the knowledge we gain from amphibians can likely be translated to human treatments.
In response to these breakthroughs, several clinical trials have been started to determine just how effective these treatments may be in human subjects. While it is still unclear exactly how translatable amphibian research may be to human medicine, it is unlikely that the fascinating regenerative abilities of our small, slimy friends will ever stop being a source of wonder to those who study them.
Nature Medicine (2018). DOI: 10.1038/nm.4502