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Nailing Regeneration

Researchers identify the signaling program that enables finger and toenail stem cells to direct digit regeneration after amputation.

By | June 12, 2013

Humans, like mice, can regenerate fingertips--especially as children.STOCK.XCHNG, JUZARAStem cells at the base of finger and toenails act as coordinating centers to orchestrate communication between the nail, bone, and nerve tissues necessary to promote mouse fingertip regeneration after amputation, according to new research published today (June 13) in Nature. Researchers found that nail stem cells use a signaling pathway important for embryonic limb development to help nerves and new nail and bone cells coordinate signaling during tissue regeneration, providing insight that may enable future stem cell therapies.

“It’s a marvelous study” that described the molecular and cellular processes contributing to mammalian regeneration, said Hans-Georg Simon, a developmental biologist at Northwestern University who did not participate in the study. The findings show that the molecular program governing mammalian regeneration resembles that already seen in amphibians—suggesting a conserved regeneration program that could be harnessed in other tissues, he added.

Unlike some amphibians, which can regrow entire limbs into adulthood, mammals have limited powers of regeneration. But mice and humans can regenerate fingertips to a limited extent—a phenomenon linked to the fact that nails, like hair and skin, are self-renewing tissues. “Very little was known about how nail epithelium cells are regulated,” explained Mayumi Ito, a stem cell biologist at New York University (NYU) who led the current study. “We knew they keep growing, but don’t know much about how it happens.”

To peer closer at nail growth and regeneration, Ito and first author Makoto Takeo, also at NYU, used genetic labeling to locate stem cells in mouse nails. These cells, unlike tissues farther from the tip of mouse digits, expressed proteins in the Wnt signaling pathway, already known to be important in nail and limb growth during embryonic development. Conditionally knocking out ß-catenin—a transcription factor downstream of Wnt—in adult mice prevented nail differentiation.

It turned out that nails only regenerated if some nail stem cells remained after the rodents’ digit tips were snipped off, suggesting that nail stem cells serve as a “signaling center” to coordinate the regeneration response of both bone and nail tissue, said Ito. Knocking out ß-catenin prevented regeneration, suggesting the Wnt pathway was critical to the nail stem cells’ role.

Loss of ß-catenin in nail stem cells also prevented nerves from growing toward the wound site—a process known to be critical to successful amphibian limb regeneration. The nerves in turn prompted the mice’s nail epithelia to secrete fibroblast growth factor (FGF), a protein that prompted the differentiation and proliferation of bone-forming cells during digit regeneration. Without signals from the nail stem cells, the interactions between nail and bone tissues failed to occur.

However, when the researchers amputated mouse digits beyond the stem cell site—but activated ß-catenin signaling—the nails still could not regenerate even though bone-forming cells were induced, suggesting that the nail stem cells secrete other factors that spur the regeneration process.

“The work really highlights that mammals don’t completely lack the ability to regenerate—it’s just that the correct developmental signaling is not turned on,” said James Monaghan, a regeneration biologist at Northeastern University who was not involved with the study. “It shows for first time how similar mammalian digit regeneration is to amphibian limb regeneration.”

Though the work provides insights into mammalian regeneration, “it is still too early to know if it will be possible to regenerate limbs severed from other spots,” noted Elly Tanaka, a regeneration biologist at the Center for Regenerative Therapies Dresden who was not involved in the research, in an email to The Scientist.

An important first step will be identifying other important molecules the nail stem cells release to regulate regeneration, a line of investigation Ito’s lab is already pursuing. Ito also hopes to determine whether transplantation of nail stem cells could aid in regeneration. But Simon expects that recreating the “cocktail” of factors secreted by stem cells will be feasible, and perhaps even enough to stimulate regeneration without the need for transplantation.

Regeneration research “is getting into a new kind of era,” said Simon, predicting that the ability to move from amphibian limb regeneration to “engineer a mammalian model system is very, very much in reach.”

M. Takeo et al., “Wnt activation in nail epithelium couples nail growth to digit regeneration,” Nature, doi: 10.1038/nature12214, 2013.

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