Stem Cells, Growth Factors, Cytokines and Skin

Stem cells, Growth Factors, Cytokines, and Skin


Popular science these days is fascinated with stem cells. Stem cell science is indeed quite revealing about the natural process of healing from damage or disease, and you can read all about growing new organs and receiving stem cell injections with dramatic effects on recovery from trauma, heart attacks, spinal cord damage, and various organ failures. And, while we are still many years away from approved therapies to repair such major insults, the evidence is accumulating and irrefutable. The effects are indeed “amazing”, even to a cold hard scientific mind.

There is one particular population of stem cells, called mesenchymal stem cells, that has a special role in healing. When there is trauma or damage anywhere in the body,

Acting as a 911 system for repair and rejuvenation, these cells are “called up” from their natural niche (in bone marrow and perivascular spaces) and migrate to the place of damage where they then act as “first responders” by coordinating the rescue operation. Only a few years ago we thought they did their primary work by differentiating into new cells (e.g. heart, liver, nerve) which is the one part of the special capability that defines a stem cell as different from other cells. We now know that this is actually a small part of the story. Their major healing effect are due to a set of chemicals they manufacture and secrete in repose to the injury. These natural chemicals are called cytokines. Acting as the local command and control operators, mesenchymal stem cells communicate with local cells in the damaged tissue to coordinate the steps of damage control, wound repair, and healing.

So, what do these stem cells have to do with ageing? We start out life with an abundance of mesenchymal stem cells. As newborns, our healing abilities are quite remarkable. Major surgeries performed on babies still in the womb are dramatic and often lifesaving, but at the same time invasive, cutting and burning through fetal skin. And yet, babies who have had such surgeries often emerge at birth with little or no scarring. This observation has long fascinated those involved with the science of wound healing. With recent discoveries in stem cell science, we now have a plausible explanation. The graph below shows the number of mesenchymal stem cells we start life with, and the number we are left with in our later decades.

Over our life span, the number of mesenchymal stem cells in our bodies declines dramatically. One might reasonably conclude that we have only 1/100th of the healing power of mesenchymal stem cells available to us at age 60 as we do at birth. This is perhaps an oversimplification, but serves as a vivid illustration of the relationship between stem cells and ageing, and provides a plausible explanation of why healing capacity diminishes over our human lifespan.

That helps to explain the skin’s response to major damaging events, like surgery. But what about wrinkles and age spots and skin lesion, including even cancer. Well, it turns out that much of that is due to accumulated damage over a lifetime. Every day, cells in your skin are damaged, resulting thousands of microscopic wounds. Photoageing (damage from the sun’s radiation) tops the list, but there are many other damaging elements in the environment around us. Chemicals (including makeup), smoking, diet, even gravity – all these play a role.

Stem cytokines and growth factors

How exactly do mesenchymal stem cells, our body’s first responders, accomplish their job? How do they know when to respond, and where to go? What do they do when they get there? Where do they hang out when they are not needed? To better understand this, we need to dive a little deeper into the topic of stem cytokines.

The medium for communication among stem cells and with surrounding cells is a group of chemicals known as cytokines. Cytokines are ubiquitous in the human body; indeed most cells make some. But mesenchymal stem cells are unique in the quantity and type they make, which alters depending on the circumstance, such as phase of healing. There are at least 500 different stem cell derived cytokines. Some of the cytokines are inflammatory, some anti-inflammatory. Some are growth factors, some are inhibitors of growth (of the wrong type, thus having a putative role in cancer prevention). Cytokines are also what the mesenchymal stem cells use to communicate with one another, and with other cells, like skin fibroblasts. Some are short distance (cells touching) and some are sent to other cells long distance. When all is said and done, it is the pattern of these cytokines that orchestrates healing (and rejuvenation).

Until just a few years ago, stem cell scientists thought that mesenchymal stem cells worked their healing magic by migrating to the place of damage, and then attaching and differentiating into (becoming) cells needed to repair the damage, e.g. become heart muscle cells to replace those that died in an acute heart attack. We now know that this is a minor part of what they do. Instead, they perform most of their magic by orchestrating other cells in the damaged tissue to repair the damage. Immune cells to clean up debris. New heart cells from heart progenitor cells. Cytokines control inflammation, and can turn it on or off. Chemokines are a particular type of cytokine that act as traffic cops at the site of injury, and work by attracting other cells to migrate there, and then activate them to begin their work.

The language of stem cytokines

There is a two-way communication between the damaged tissue and the rescue team of mesenchymal stem cells. Much of Cellese’s work focuses on replicating this in the laboratory. Cellese scientists attempt to understand the language of mesenchymal stem cells as they communicate with one another and with other cells, including keratinocytes and fibroblasts within skin. Cytokines can be grouped functionally, like letters in a word, which together convey a message. And while each word has a meaning, when you put them into a sentence you get finer shades of meaning. There is both a vocabulary and a syntax of stem cytokines. Once the language is understood, it is possible to communicate with the stem cells in the laboratory. This “talking to cells” may sound like the stuff of science fiction. And while we won’t be teaching them English any time soon, the language metaphor is quite helpful. When we communicate with them, via cytokines, they communicate back, via cytokines. If you know what cytokines you want them to produce, you need to understand their language.

We term this the lingua cytokinum- the language of cytokines.

Ageing skin: health and aesthetics

What does all this have to do with ageing skin, health, and aesthetics? Ageing skin reflects two things. One is the amount of time we have spent on the earth accumulating damage (our chronologic age), and the other is our diminishing ability to respond to damaged skin with our inborn, restorative system of healing (which reflects age, but also health). At any age, healthy skin is judged more aesthetically appealing than unhealthy skin. And because ageing skin is more prone to look unhealthy, the logic gets tied together; healthy skin is seen as “younger”. Which brings us back to the divergence between chronologic age and apparent age. Again, we cannot stop ageing from occurring, but there are things that we can do to improve our skin health. We may not be younger, but we can look younger.

How do we do that? General health affects skin health, so get the rest of the body healthy avoid tobacco, excess alcohol, and toxins of all sorts. Keep your skin clean, moist if too dry, dry if too moist. Supply your skin with added nutrients that make it thrive, especially those with potent antioxidant effects.

But wait …what about those mesenchymal stem cells and their cytokines? Now that we understand how their damage control work relates to skin health, is there something more we can do?

The answer is yes.

One theoretical way to restore the natural healing ability of our whole body (including skin) would be to increase the number of mesenchymal stem cells in the body, so that more are available to migrate to damaged areas. That is a complicated process, and in fact is part of what happens with a bone marrow transplant. But such transplants are risky and costly, and thus rese4rved for life threatening diseases such as certain leukemias.

But we have discovered a simpler path, without the risk and expense. One that is tuned to rejuvenating skin (our current mission here at Cellese). Recognizing that it is the cytokines that provide a major mechanism of action (and the bulk of the benefit) of mesenchymal stem cells, we discovered that we can take mesenchymal stem cells from healthy young humans and grow them in the laboratory, under special conditions that mimic theior natural environment. We can talk with them, and convince them to secrete cytokines in abundance. We can then harvest these cytokines and from them create a powerful new class of active ingredients for skin therapeutics.

Stem cytokine farming

Imagine, if you will, a farm. Not fields of wheat or soybeans, but fields of mesenchymal stem cells, millions and millions of them, growing on microscopic spheres in vessels of nutrient broth. The mesenchymal stem cells multiply and spread out, sometimes jumping from one sphere to another if theirs gets overcrowded, colonizing more spheres. Sounds like a scene from Star Trek? Turns out it is similar to what happens in bone marrow during fetal development.

Every few days we harvest the stem cytokines which they have “exported” into the between cells space as they communicate or signal to one another in keeping with their healing agenda. We further process to separate and isolate these cytokines, cold filter, purify, and preserve them.

Now it gets a bit more complicated here. Mesenchymal stem cells modify their cytokine output based on what is needed, and where. Healing a skin wound has phases, including an inflammatory phase and an anti-inflammatory phase. The right cytokines are needed at the right time. Too much, or not enough, of one or the other, at the wrong time, and things tend to go awry. The wrong matching of the stage of healing to cytokine pattern could do more harm than good. An extra step is needed that alters the cytokine “code” to optimize the pattern of individual chemicals for different phases, stages, and types of healing. The demolition crew needs to show up before the rebuilding crew does their job, not after!

Also, some cytokines are associated with more of a scarring type of healing response. While others (in the same family) promote a scar free healing. All of this points to the need to understand cytokines, not as individual molecules, but in patterns.

Stem cytokines as regenerative therapeutics

We can harvest these specific cocktails of stem cytokines and put them on skin that has been damaged. Everything associated with the healing of wounds is accelerated. Wounds heal much more quickly in the presence of these types of cytokines. Mop up cells (called macrophages) arrive to clean up the damage, then leave. Basal cells (the innermost layer of epidermis) are stimulated. Fibroblasts (cells that secrete collagen and elastin) migrate to the area. Matrix (the nutrient rich fluid between the cells) is restored to a healthy state. Collagen fibers, a large part of the scaffolding of skin, are manufactured in this matrix. New skin cells begin to appear, growing from deeper (basal) layers upward.

How do we know it works?

Let’s revisit the hypothesis that aging skin reflects accumulated (and ongoing) damage, that as we age our capacity to defend against such damage diminishes, and that one aspect of the less vigorous response can be seen in the number & function of our natural defense system reflected in mesenchymal stem cells and their chief export – stem cytokines. There are different types of scientific evidence we can bring to bear on the issue, including data from in vitro (laboratory) and in vivo (live humans) experiments. All of these are important, and we want you to have access to all that information, so we plan to add compendia of research with documents and links.