Glial Cell Behavior Critical to Proficient Central Nervous System Regeneration

Why can species such as salamanders regrow organs and limbs while mammals cannot? This proficiency even extends to portions of the central nervous system, such as the spinal cord. In recent years, researchers have made good progress in understanding exceptional regeneration, finding that, for example, differences in the behavior of immune cells called macrophages are essential to regrowth. In the central nervous system, glial cells are somewhat analogous to macrophages in other tissues, and in the research noted here, scientists report on evidence for an equivalent importance in mammalian versus salamander regenerative capacities.

Given the macrophage and glial cell connection, this area of comparative biology is moving of late from speculative to relevant to clinical development. Numerous research groups are investigating the alteration of macrophage and glial cell behavior in order to spur greater regeneration in mammals. These cells can be classified by their behavior, either aggressive and inflammatory while seeking out pathogens, or more focused on aiding regeneration. Both behaviors are needed, but in mammals, and in the old, there is too much of the first type and too little of the second type of behavior. In learning to adjust cell behavior to change this imbalance, the foundations may be laid for more profound enhancements of regeneration in the years ahead, building on what is learned from salamanders.

One of the most vexing problems with spinal cord injuries is that the human body does not rebuild nerves once they have been damaged. Other animals, on the other hand, seem to have no problem repairing broken neurons. Researchers have studied an amphibian known as the axolotl or Mexican salamander. Captive-bred axolotls are frequently used in biological research, both to learn from the animal's remarkable ability to regenerate body parts and to help inform conservation efforts.

When an axolotl suffers a spinal cord injury, nearby cells called glial cells kick into high gear, proliferating rapidly and repositioning themselves to rebuild the connections between nerves and reconnect the injured spinal cord. By contrast, when a human suffers a spinal cord injury, the glial cells form scar tissue, which blocks nerves from ever reconnecting with each other.

Researchers traced the molecular mechanisms at work in each case. They found a particular protein called c-Fos, which affects gene expression, is essential to the processes axolotls use to repair injured nerves. While humans also have c-Fos, in humans the protein functions in concert with other proteins, in the JUN family, that cause cells to undergo reactive gliosis, which leads to scar formation. In axolotls, this molecular circuitry is carefully regulated to direct axolotl glial cells toward a regenerative response instead.

"Our approach allows us to identify not just the mechanisms necessary to drive regeneration in salamanders but what is happening differently in humans in reposes to injury. In addition to spinal cord regeneration, our work also focuses on other forms of regeneration including scar-free wound healing and limb regeneration."



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