New research funded in part by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases has uncovered chemical signals that drive the regeneration of lost digit tips in mice. The findings, published in the journal Nature, could eventually lead to the development of novel treatments for amputees.
While salamanders and newts are well known for their ability to regenerate lost limbs, people’s capacity to regrow lost body parts is minimal. We can only regenerate the tips of our fingers and toes, and only if part of the nail remains.
Scientists have long wondered why the nail is so crucial for regenerating our fingertips. Now, a team of scientists led by Mayumi Ito, Ph.D., of New York University School of Medicine, has uncovered some answers.
Working in mice, Ito’s team focused on the region at the base of the nail, which is populated by a type of cell called nail stem cells. These cells are known to drive the continual growth of nails, but Ito’s team discovered that they are also involved in the more complex process of regenerating a lost digit tip.
The researchers began by examining the role played by a signaling pathway called Wnt on the growth of nails. They chose to study this pathway because it is involved in limb formation in mammalian embryonic development, as well as limb regeneration in amphibians.
They found that the Wnt pathway was active in mouse nail stem cells and was necessary for nail growth. When they blocked the pathway, the mice’s nails stopped growing.
They next tested Wnt’s role in the regeneration of mouse toe tips. Typically, mouse toe tips return to their normal structure five weeks after they are clipped off, as long as some of the nail stem cells and the underlying layer of cells called the nail epithelium are left behind. But when the researchers blocked the Wnt pathway, neither the nails nor the toe tips regrew, showing that Wnt signaling is crucial for regeneration.
"What we learned from these experiments is that the nail epithelial cells form a sort of command center that coordinates the formation of the new digit," said Dr. Ito. "Using the Wnt signaling pathway they set in motion the complex process of building tissues and assembling them into a new, intact toe tip."
Ito’s team next set out to examine the role of nerve cells in digit regeneration. They had noticed that in control mice, nerve cells began to extend into the regeneration site following toe tip amputation. But when the Wnt pathway was blocked, nerve cells were not drawn to the wounded area. The researchers knew that laying down new nerve cells was crucial for limb regeneration in amphibians, so they wanted to examine their role in mammals.
When they removed nerves from the mice’s toe tips prior to clipping them, they found that the toe tips failed to regenerate. Additional experiments revealed that nerve removal decreased the level of a growth factor that causes cells to grow and multiply.
From their results, Ito’s team concluded that the Wnt pathway triggers digit tip regeneration by signaling the formation of new nail from stem cells found at the base of the nail. The regenerating nail epithelium then draws nerve cells into the wound site. These nerve cells—by stimulating the release of a growth factor—help promote the formation of the other tissues, such as bone, muscle and tendons.
"What’s striking about our findings are the parallels between what we know about the signaling pathways governing limb regeneration in amphibians, and what we’ve uncovered here in a mammal," said Dr. Ito. "The similarities suggest that we may one day be able to harness the process and develop new treatments for amputees."
This research was supported by NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant number R01-AR059768), the Ellison Medical Foundation, and New York University School of Medicine’s Ronald O. Perelman Department of Dermatology, Department of Cell Biology, and Helen and Martin Kimmel Center for Stem Cell Biology.
Takeo M, Chou WC, Sun Q, Lee W, Rabbani P, Loomis C, Taketo MM, Ito M. Wnt Activation in Nail Epithelium Couples Nail Growth to Digit Regeneration. Nature 2013 Jul 11;499(7457):228-32. doi: 10.1038/nature12214. PMID: 23760480
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