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Nailing a New Niche of Stem Cells

If my mother-in-law hadn’t just yanked off a toenail, I might not have noticed the news release from researchers at the University of Southern California’s Stem Cell Regenerative Medicine Initiative. Their elegant experiments in mice reveal the heretofore unknown collection of stem cells that enable the rodents, and presumably us, to regrow our nails.

Krzysztof Kobielak and colleagues (first authors are Yvonne Leung and Eve Kandyba) report their findings in the October 21 Proceedings of the National Academy of Sciences. It is unfortunately behind a paywall, so I will enlighten you.

Nails, skin and its glands, and hairs descend from the same layer of the embryo, the ectoderm. The nail is the last to reveal its stem cell secrets. Skin renews constantly, hair cycles every few months, and sweat glands don’t replace cells often if at all. A nail is the only ectodermal derivative able to completely regenerate if ripped totally out, as my mother-in-law just did.

It turns out that a nice niche of stem cells enables nails to regrow. This, to me, is the most fascinating part of stem cell science – discovering new aspects of anatomy and physiology, especially how parts initially form or regenerate.

MOUSE MANICURES
The researchers created transgenic mice that had DNA sequences encoding:
• A keratin, expressed in the ectodermal derivatives
• Green fluorescent protein (GFP) from jellyfish, a standard way to track cells
• A protein that confers resistance to tetracycline antibiotics

The genetically modified mice had skin, nails, hair, and sweat glands that initially glowed greenly. But after a bit of development, and then a course of doxycycline, the color faded in all but the stem cells, which retained the GFP marker because unlike other types of nearby cells, being stem cells they didn’t readily divide. (The color became diluted as neighboring cells divided without further stimulation to express GFP.)

The stem cells form a distinctive ring in an area of a nail called the proximal fold, the bit of nail/skin boundary just underneath the tip. The investigators named the cells “nail proximal fold stem cells.” Production of keratin #15 distinguishes the stem cells, a little like hair colors. (Most types of mammals have about 50 keratin genes.)

To see how a nail regenerates following damage, the investigators induced “nail plucking injury,” presumably under non-torture conditions, and watched what happened. That meant a transcriptional profile, a look at the messenger RNAs made as the nail regrows, and compared profiles of healthy nails as well as in surrounding skin for both situations.

A lot goes on in nails. Hundreds of genes blink on and off, just to keep nails growing normally. As expected, transcriptional profiles change following injury. After subtractions eliminated housekeeping gene expression, two genes that regulate bone morphogenetic protein (BMP), called Bambi and Decorin, emerged as the controls of nail growth. Normally they dampen production of BMP, which favors growth of the skin around the nails. But whack off a nail and expression of these genes, and of the BMP that they control, increases.

So the stem cells can do two things: favor skin, or favor nail. And they can change what they do to suit environmental circumstance.

To test the findings further, the researchers bred mice that couldn’t make much BMP. And the animals had puny nails, especially at the tips, with overgrowth of surrounding skin.

The maimed mice regenerated their nails in just 2 weeks. I imagine things will move at a slower pace for my mother-in-law.

OUTGROWTHS
As for most stem cell discoveries, knowing about nail proximal fold stem cells inspires the imagination.

• Understanding the signaling behind the shift from making-skin to making-nail may suggest new drug targets and candidates for assisting regeneration of human fingertips. Humans can regenerate fingers, but in a limited way compared to, say, the abilities of a starfish.

• Stem cells likely control shifts in repair at other bodily tissue interfaces. Perhaps we can tweak them, too, in therapeutic ways.

Otzi, the ice man
Otzi, the ice man

• Identifying the dead. Stem cells might protect DNA in a corpse, compared to a cell that normally divides often. Sampling stem cells from nails to confirm the identity of a corpse might be easier than obtaining other tissues. I’m thinking of the fuss over the DNA extracted from teeth and hair of outlaw Jesse James and the pelvic bone from 5300-year-old  Ötzi the Tyrolean Iceman.

• Cosmetic possibilities. Might a coating of BMP-spiked color or hardener halt nail growth, preserving the perfect pedicure?

DEFINING STEM CELLS
Finding an accessible stem cell niche, even in a structure as seemingly non-vital as a toenail, is important, because tweaking the fates of any stem cells’ daughter cells might provide therapeutic cells tailored to the individual. Imagine bolstering a failing heart with cells from one’s nails.

Media gripe: many articles still define stem cells as “turning into any cell typ,” No need for links, just google that phrase.

If stem cells turned into “any cell type,” they’d soon be depleted. Rather, when a stem cell divides, it produces another stem cell (“self renewal”) and also gives rise to daughter cells that may go on, perhaps dividing more, to specialize.

The biological significance of a stem cell is the ability to perpetuate its stemness. In the illustration above, only the cells ringed in purple are stem cells.

An analogy. If turkey, dried bread hunks, butter, celery, potatoes, green beans, mushroom soup and other Thanksgiving fare spontaneously assembled into casseroles and such, and people ate it all, there’d be nothing left for seconds or thirds unless the fridge magically filled with more of the basic ingredients. Like the gobbled up Thanksgiving feast, an organ that uses up its stem cells and must grow to stay alive is in trouble. And that’s why stem cell science is so exciting — it uses our body’s natural reserves.

OK, so I’m not great with analogies. Have a happy Thanksgiving, and thanks to all readers of DNA Science!

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