As human stem cells and their role in skin physiology, wound repair, aging, and rejuvenation is the subject of our own work, we have a lot to say on the subject. As our goal here is education at a consumer level, we struggle mightily to express complex concepts and research results in terms that can be appreciated by all, including non-scientists. But sometimes fine shades of meaning have big consequences, and we don’t want to compromise on the bare faced truth mission either. It is frankly a challenge, and I’m sure we fail for the most part. So we apologize in advance and ask you to bear with us. Hopefully we will get better at this as time goes on.
In a prior post we introduced the subject of mesenchymal stem cells. Next we will take you a bit further down the path of understanding what these particular stem cells have to do with skin and aging. I thought I would put this in outline form. See if this makes it any easier to digest. Here goes.
Not all stem cells are the same. There are many varieties.
Mesenchymal stem cells (MSC’s) are one type; they form a key part of the human body’s defense against injury and stress.
MSC’s can be found in many places in the body – bone marrow, fat, tooth roots, around blood vessels, etc. Each of these are called “niches” and reflect the home environment of that type of MSC. There is increasing evidence that marked differences exist in the biology of MSCs that are dependent on the tissue of origin. Indeed this niche factor appears to be the main source of variation in the biological properties of MSCs (De Bari et al., 2008; Augello, Kurth & De Bari, 2010).
Thus, not all MSC’s are the same.
MSC’s migrate to damaged areas of the body. There they act as first responders. Their primary role is command and control – telling local tissue what to do, and organizing cells of the immune system which are the worker bees.
All communication among MSC’s and between MSC’s and other cells (e.g. damaged skin cells) uses biochemicals called cytokines.
There are hundreds of cytokines, each with a specific message (e.g. “hey fibroblasts, let’s make some more collagen”). Multiple messages are in play at any time in an MSC mediated response. The messages are tightly coordinated so they reach the right cells at the right time for the proper work to be done. Some are very short distance and some are medium or long distance.
Cytokines can be classified into families. Some are growth factors (“make more cells”), some are chemokines (“bring me some phagocytic cells”), and many are involved in protein synthesis inside cells they target.
MSC cells themselves can differentiate into needed cells for rebuilding damaged tissue. But it turn out that that is a minor part of what they do, not the major thing. In skin in particular, MSC’s as bricks in rebuilding is unlikely except in severe damage (e.g. burns).
Aging skin reflects both intrinsic cell and tissue level changes (senescence) and a process of continual damage (e.g. from sun, chemicals, disease) and repair (via several mechanisms, including calling 911 to bring MSC’s to the area).
There are unique MSC-like cells that live in very small numbers in the bottom of hair follicles. This is their “niche” (remember, not all MSC’s are the same). There are also perivascular (around blood vessel) MSC’s in the dermis of skin (deeper).
These “local” stem cells have particular roles to play in maintenance of growth, and replacing senescent cells (all cells die of old age eventually). But in terms of damage, other MSC’s migrate to the area from guess where? The bone marrow. Seems like that is the special role of that particular MSC niche.
That scenario will be no surprise to those who know that the bone marrow is also where all the blood cells (red corpuscles and white immune system cells) are made and exported via the blood stream to perform functions throughout the body. In fact, bone marrow MSC’s and bone marrow “hematopoetic” stem cells live in very close proximity in the bone marrow. These are the same cells that get replaced when a “bone marrow transplant” is performed.
When skin undergoes repair, all these mechanisms must act together in a coordinated fashion. Again, that control seems to be the specialty of marrow-derived MSC’s secreting very specific patterns of cytokines. Those cytokine patterns are what determines that the right thing happens at the right time. E.g. you don’t want to build new cells until you have mopped up the debris from damaged tissue. That would be like painting over old peeling wallpaper. Ask your local contractor. Demolition happens first, then rebuilding.
When you hear about products that contain stem cells, you should ask several questions. First, you should read Dr. George’s post about plant stem cells (don’t work), creams that have nothing to do with stem cells whatsoever except using it as a deceitful marketing term (e.g. Biologic’s Stem Cell Cream). You can filter these out right away.
That leaves you with human stem cells. Now, you will not find cosmeceutical products on the market that contain human stem cells. That would be considered a “biologic” by FDA standards, and would be regulated like a drug or device. The reason is that whole cells contain (other people’s) DNA, and may also carry disease.
While human stem cells themselves won’t be in any products, they can be grown in culture (in vitro, or outside the body) in a laboratory. When they do so, if they are well fed and happy, they tend to divide to make new daughter cells. When they are doing so, they communicate with one another via cytokines. Remember the messenger molecules we spoke of above? This is the basic language of stem cells. Again, if the conditions are right, they chatter away as they “expand” in culture (more of them, coming closer together”). As they start to crowd up against each other (we call that “confluence”) the message changes. More of those “short distance” cytokines are produced. Some are transferred from one cell to next one touching it (we call that a “paracrine” message). The MSC’s start to slow down their proliferation when the numbers reach confluence. At this point the cell biologist may transfer some of those cells to new flasks, where they will be less crowded, and will resume proliferation. This is a called a “passage”.
Now, if you remove some of the nutrient rich fluid that bathes the MSC’s in culture, you will find that it contains a lot of cytokines. This is called conditioned medium. It is cell growth medium conditioned by the many cytokines secreted by the MSC’s. It’s like capturing a whole bunch of cell-to-cell conversations all at once. An analogy might be your cellular telephony system. If you could grab 5 second sample of all the conversations going through one cell tower, it would indeed be a “tower of babble” But your cell system is clever enough to sort all those words into the right pathway to make a conversation.
So, here is the discovery that led to a whole new generation of anti-aging skin care products. If you take that conditioned media and put it on skin, you can observe immediate improvements in skin texture, tone and color. If you keep applying it, you will see structural changes (increase collagen production) with diminution of wrinkles. It has interesting “side” effects. Minor cuts and abrasions heal very quickly. Angry red areas seem to disappear.
That defines the first generation products whose key active ingredients are made by stem cells in vitro. But that is only the start. We now are gaining insight into the stem cytokines themselves, and the patterns they form. We know that they talk about a lot more than growth, and if can discern what they are saying and how they say it (in other words decipher their language) we can change the cytokine composition of the conditioned medium. We can them communicate back with the MSC’s in culture in their language. In doing so (I will leave out a lot of proprietary steps here) we can get them to change their message by responding to ours. We can optimize it for different situations. So, it is no longer one product (a bunch of cytokines) but a very clever set of stem cells making products for whatever condition we require.
This is a lot for one post. I’m up to about 1,500 words. I will leave it here for now, and let interested folks who have read this far digest and ask any questions you may have.
One last thing – this is very exciting stuff, and has many impacts beyond skin & aging. This is not mere cosmetics – this is core cellular physiology. And how grand it is (for a change) that skin science gets to be on the forefront of research rather than on the back burner.
Await your comments.