皮肤为何能一生相伴？| Nature Podcast

来源：Nature自然科研

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Interviewer: Nick Howe

Skin ageing is a fact of life, so how does it happen? Well, this week, I’ve been trying to find out, but before I get into that, I’ll start by describing how skin is structured. So, skin is divided into layers. The outermost layer is the epidermis, the protective barrier against the world. At the base of the epidermis are stem cells which use sticky proteins called collagen to secure the epidermis to the layer below. These stem cells are responsible for replenishing the epidermis by differentiating into all kinds of specialised skin cells. As the top layer of skin is the barrier between our body and the elements, it frequently receives damage by things like UV, so the cells at the top need to be restored by the stem cells at the bottom. This restoration allows the skin to regenerate itself by removing damage, which also keeps the skin looking young. But the exact mechanisms of how the stem cells themselves stay damage-free  aren’t  clear.  

This week in Nature, a new study may help clear up how the skin maintains a healthy pool of stem cells and its youthfulness.  The authors of the paper weren’t available, so I caught up with James DeGregori, who has co-written  a News and Views article on the topic, to find out more. 

Interviewee: James DeGregori

So, what this paper has shown is when cells in our skin receive damage, that there’s a quality control mechanism where that damaged cell will downregulate one particular collagen protein. 

Interviewer: Nick Howe

This collagen protein is called COL17A1 and it helps the stem cells at the base of the epidermis remain anchored to the layer below. When one of these stem cells is damaged, it produces less of the COL17A1 meaning the cell isn’t stuck as tightly, which allows its undamaged neighbours to lever it away from the bottom layer. The other healthy stem cells then divide horizontally to take up the space. Although these damaged stem cells are pushed out, they still have a role to play. 

Interviewee: James DeGregori

It’s not that they die, they just lose their ability to maintain themselves as stem cells and instead they become the functional outer layer of our skin. That has a function – it still protects us – but it’s destined for eventually shedding off of our body. 

Interviewer: Nick Howe

These epidermal stem cells are always in competition, and those without enough of the sticky collagen protein lose the battle and get pushed. In this way, only the fittest cells survive and by removing the damaged cells, it makes sure skin is renewed from a pool of healthy stem cells. Of course, our skin doesn’t stay youthful forever and eventually thins, wrinkles and discolours. So, after a lifetime of damage it appears that the balance between cell renewal and the rate of cell damage shifts. 

Interviewee: James DeGregori

Eventually, the rate of damaged cells that accumulate outpaces the ability to purge them and eventually if your neighbours are even damaged, they’re no longer able to outcompete another damaged cell and so the damaged cells basically outpace the undamaged cells. 

Interviewer: Nick Howe

Ultimately, the overall levels of the sticky collagen decline in all the stem cells and the competition slows down. So, there aren’t enough healthy stem cells left to regenerate the skin. Also, due to less attachment of cells to the layer below, the structure of the skin starts to deteriorate. The authors of the new research specifically showed that the sticky collagen COL17A1 is key to the competition between healthy and damaged stem cells. When this collagen was artificially supressed, cells were more likely to be pushed out. 

Interviewee: James DeGregori

And they further showed that by restoring collagen, the same collagen, to an older, damaged cell, they could prevent the purging from happening. So, the collagen seems to be sort of the key regulator of the fitness of these stem cells. 

Interviewer: Nick Howe

While this study may give a plausible mechanism for skin maintenance, most of the research was done in mouse tails, so how applicable is this to humans? James thinks mouse tails are a good model for human skin and says the authors have shown their results in more than just mice. 

Interviewee: James DeGregori

They also used three-dimensional models of human skin, where they can create human skin in a culture dish, and they showed that these same processes were active even in human skin. Of course, this was done in a culture dish, but I think it’s the next closest thing to actually doing it in an animal. 

Interviewer: Nick Howe

So, if we have this understanding of the mechanism of how skin is kept young, is there a possibility we could increase the amount of this collagen protein and promote the process of purging the damaged cells? 

Interviewee: James DeGregori

This group actually, at the end of their paper, they screened for compounds that increased the expression of this protein, and they showed that at least with ultraviolet light-induced damage, that they could actually protect the cells and maintain better integrity of skin by treating skin with this compound. 

Interviewer: Nick Howe

Although the two compounds show promise for increasing the production of the sticky collagen, we’re still a long way from the fountain of youth. These compounds promoted wound healing, an important part of skin maintenance but not the only part. Also, these compounds would have to go through all the relevant drug testing processes before they could be used. James thinks, though, this study represents an important step forward in our understanding of how skin is kept youthful and disease-free by preventing the accumulation of damaged cells. 

Interviewee: James DeGregori

I think this is a very exciting paper because it provides a specific mechanism for how youthfulness is maintained in terms of this purging of damaged cells, and I think this could be very useful because not only is damage to cells a factor as we get older, but it’s a factor when we get exposed to, for example, ultraviolet light, which many of us are exposed to even on a daily basis. So, if we can have some way of improving this elimination, that could be useful for prevention of skin cancer and eventually it could be useful for the long-term maintenance of what’s a very important barrier between us and the outside world. 

Interviewer: Nick Howe

That was James DeGregori. You can find his News and Views article and the original research paper over at nature.com. ⓝ

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