The axolotl’s ability to regrow limbs make it widely studied by scientists hoping to understand regeneration and perhaps mimic the process for healing injuries in people. (Photo: wikimedia commons)

Yes, it’s true; the axolotl is an oddly adorable salamander but it is its ability to regrow complex structures like the legs, tail, retina and spinal cord after injury that fascinate researchers. Unlocking the mysteries of regeneration in the axolotl may some day help point the way to therapeutic strategies for tissue regeneration in humans. And in the May 20th issue of the Proceedings of the National Academy of Science, a research team from the Australian Regenerative Medicine Institute reports on progress toward that goal: they demonstrate that a specific white blood cell, the macrophage, is critical for the axolotl’s ability to regrow its limbs.

When you hear “white blood cells” you might think “fighting off a bad cold” and probably not “re-growing limbs”. The macrophage, which literally means “big eater”, does in fact act as a first line of defense against foreign invaders. They travel the body devouring viruses and bacteria and then pour out signaling proteins that sound the alarm to the other cells of the immune system. But macrophages have many more functions such as wound healing in which they help clear out dead cells and support cell growth for restoring tissue.

Wound healing and tissue regeneration are thought to use similar mechanisms. So in this study, the researchers removed macrophages from the axolotl and then amputated a limb. The result: in all cases, no new limbs. When the scientists added macrophages back and amputated more of the limb, that limb regenerated normally. This confirmed that macrophages are required for this remarkable process.

So what’s the difference in macrophage function between mammalian wound healing and amphibian limb regeneration that might explain the axolotl’s superior abilities?

The researchers found that in the first 24 hours after amputation, macrophages secrete proteins that both activate and inhibit the immune system. In wound healing, on the other hand, macrophages are known to secrete activator proteins for several days and then later they release proteins that help slow down the immune response. The authors speculate that stepping on both the accelerator and the brake of the immune system creates the right cellular conditions to kick-start the regeneration process.

Despite these intriguing results, re-growing a severed human foot is a long ways off. Still, as James Godwin, the paper’s first author, said in an interview with The Scientist:

This really gives us somewhere to look for what might be secreted into the wound environment that allows for regeneration.

At CIRM, we’re big fans of this type of fundamental developmental biology research. CIRM grantees like Gage Crump of USC, who has a New Faculty award to study regeneration of facial bones in the zebrafish, are deconstructing how nature builds tissues to help inform the development of stem cell-based therapies that will repair our bodies after injury or illness.

Here’s a 30 second video of Dr. Crump explaining his regeneration research:

T.D.