This is the first in a series of in-depth articles exploring the science of growth factors, cytokines, and stem cells in aesthetic medicine
dermatology, and skin care… learn about EGF, IGF, VEGF, PDGF, FGF, and the whole fascinating TGF-B family. Learn about cytokines, mRNA’s and other things made by stem cells as they communicate with other cells to orchestrate regeneration.
Regular readers of BFT know that Drs. John and George are stem cells scientists who got interested in skin care as a spinoff of their work in diabetes. We are bench scientists as well as research docs, and recently opened a research clinic in Newport Beach, California. You can read one of our papers on the subject here.
We have developed a proprietary stem cell “platform” that allows us to harness the quite spectacular cleverness of the human organism’s natural repair and regenerative system (bone marrow-derived mesenchymal stem cells) with the end result being an infinite array of growth factor and cytokine cocktails, each containing hundreds of human growth factors & cytokines, in precise patterns, each tuned to address a particular issue – be it wound healing or anti-aging. Members of our team are also inv
olved in the encapsulation of stem cells for implant into diabetic animals or humans. But the skin applications are really a wholly different matter. What we create for dermatology and aesthetic medical applications is a completely cell-free admixture of cytokines / growth factors that is added to other medically proven ingredients to create skin care products.
The human stem cell-derived growth factors are completely natural to humans. Organic if you will, in that they are a perfect molecular match to the same growth factors our own bodies make. That means that allergic reactions to these molecules are pretty much nonexistent. This would put them in an entirely different category that, say, snail “growth factors” from non-human members of the animal kingdom, making them “xeno” proteins and quite prone to causing allergic reactions.
UPDATE: FOR NEW PRODUCTS BASED ON STEM CELL GROWTH FACTOR TECHNOLOGY PLEASE SEE AnteAge.com.
Our human cells make hundreds of different cytokines & growth factors, which function as signaling molecules from cell to cell, and 
which also control metabolic machinery within cells. For instance, a family of growth factors (GF’s) named fibroblast growth factors (FGF) is responsible for stimulating fibroblasts in skin to make more fibroblasts (proliferate) and manufacture more matrix (hyaluronic acid, collagen, elastin). Generally a good thing for skin. Epidermal growth factor (EGF) similarly causes skin cells to proliferate. Also a good thing, generally speaking. Except when it isn’t. For instance, giving pure EGF unbalanced by other growth factors may plump skin but the quality of that skin may diminish. More on that in a future post. Our work suggests that growth factors and cytokines need to be in a pattern that matches what nature intended – matched to an agenda (genetically, and in dynamic response to conditions like environment, injury, etc).
collagen scarring
One of the most profound lessons in all this is that aging and inflammation go hand-in-hand and especially in our largest organ – skin (so called skin’flammaging). Inflammation is mediated largely by cytokine patterns, which communicate and control the immune system (e.g. cross talk with white cells), and growth factors are part of this. Inflammatory cytokines are helpful for early stages of would healing, but in later stages actually inhibit healing or cause scarring and fibrosis. Fibrosis means that collagen fibrils are oriented improperly, distorting skin architecture, making it less elastic; not a pleasant aesthetic. Inflammatory cytokines may give temporary benefit (from puffing up skin which hides wrinkles) but are actually pro-aging, not anti-aging.
More than a decade ago, skin care products started appearing based on growth factors derived from fibroblasts (not stem cells). Typically these use fetal foreskin derived fibroblasts (ethical & sensory yucch) in the lab, rather than stem cells. Familiar high end bio-derm products like TNS from SkinMedica are based on this technology. There is good research to support a positive effect. But it is notable that certain stem cells produce 10-50x the concentration of key GF’s compared to fibroblasts. This makes sense when uyou realize the different roles these cell types play in wound healing and regeneration. Fibroblasts are really the corporals in that war, taking orders from the generals – the stem cells. Stem cells bark the orders, fibroblasts listen and do the grunt work.
Our own research has focused on the benefit of stem cell derived growth factors and cytokines (GF&C’s). What we discovered is that
a mixture that tilts the balance toward anti-inflammatory GF&C’s provides strong anti-aging and aesthetic benefits. No surprise there. our more recent work, still in clinical testing, focuses on stem cell derived admixture repair of scars, rosacea, acne, melasma, hyperpigmentation, and a host of other skin conditions. We have also recently discovered a way to stimulater follicle regeneration and hair growth using the stem cell platform (currently in testing).
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 GF&C’s.
Growth Factors live in Families
There are hundreds of cytokines & growth factors, 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. 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.
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.
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.
Please bookmark BFT so you can come back and read the whole series.
UPDATE: FOR NEW PRODUCTS BASED ON STEM CELL GROWTH FACTOR TECHNOLOGY PLEASE SEE AnteAge.com.
Hi,
Should we be concerned about the size of growth factors molecules for external application even with microneedling ? e.g. EGF is about 70,000 daltons – isn’t it too large to penetrate epidermis?
Thank you
Molecular size, polarity, and hydrophilicity has a lot to do with what does and does not get past the first few layers of cells of the stratum corneum. The old rule used to be that things larger than 50 daltons were doomed. That would rule out all but the smallest of molecules. But we have learned in the past decade that many large molecules penetrate quite nicely, especially if you combine them with penetration enhancers. If you wrap your molecules in a lipid envelope it can sneak into the spaces between cells which is lipid soluble. You have heard of liposomes – one type of that. It helps to make the substance electrically neutral. You can also do things to disrupt the barrier. Some chemicals do that = solvents like DMSO do that very well.
Now, here is the advanced lesson. Human Growth factors have something quite special about them that other types of skin actives don’t. Cells, including skin cells that are still vital, have receptors on them that detect the bio-signaling molecules. That is what their natural function is – cell-to-cell communication. Now, one part of that is amplification. Let’s say one molecule gets into the epidermis and attaches to the corresponding receptor on a cell. That cell may respond in a number of ways, including making many more molecules of that same chemical (autocrine amplification) and exporting that to neighboring cells. So one molecule now has the effect of 100 molecules. This is one of the things that makes GF’s special. You won’t get this with other skin actives.
Here is what we do to help penetration. We wrap all our GF & cytokine proteins in lipid envelopes (nano-liposomes), and add other penetration enhancers, plus some other tricks that ramp up the autocrine amplification mechanism. It is all very nifty, and in some ways mimics nature’s own way of managing these matters.
And the microchannels you make with microneedling are micron sized so big enough to pour tens of thousands of any large molecule down the hole. Which makes it both powerful (pour the right stuff) and potentially dangerous (pour the wrong stuff).
drjohn,
how can one be sure that using the antiage serum is safe? isn’t this just like every other website touting their anti age products as safe and effective? how can we be sure that using antiage isn’t going to be more harmful than good? thanks.
Fair question. Here is the answer – we performed a formal clinical study on AnteAGE with 50 subjects followed over 6 months. No adverse reactions, excellent benefits (you can read about those elsewhere). Then we started selling AnteAGE and variants of AnteAGE widely. With users in the tens of thousands, we have not had a single notable adverse reaction. This is called post marketing surveillance. But wait, there’s more. We are the only company I know that has its own research clinic (Newport Aesthetics Research) where we continually monitor the safety and efficacy of AnteAGE alone and in combination with lasers, microneedling, IPL, Venus Freeze, surgery, and a host of other interventions. Consider us fussy about details. My point is this – when you have a couple of research docs in charge, rather than marketers, you tend to get a lot more attention paid to details of basic and clinical science. We are truly the odd birds of this industry.
Thank you John. For those of us that wish to take the noninvasive approach to aging gracefully, it’s a confusing industry. You want to put your trust in your dermatologist but then you research and find that perhaps what he or she sold you isn’t the best option. Would you have your mother and/or spouse use the AnteAGE alone?
We teach at academic conferences of dermatologists and plastic surgeons. We know exactly what you are talking about. In fact most of the skin care products sold at a dermatology clinic or medi-spa is chosen by a staff nurse or aesthetician or office manager. Most physicians don’t get involved. When they do, it is often when salespeople come to the office. Education about the basic science of skin care is a major issue, in our view. On a positive note, we are seeing the beginnings of a new trend. More and more we are getting inquiries from doctors, and they seek us out a trade shows.
My wife uses AnteAge daily, and has done for years. So does my partner, DrGeorge, and his wife. DrGeorge was the first subject in our clinical trials, and for him it cured a very advanced and troublesome case of rosacea. There are many other members of my extended family and many friends who are “addicted” to AnteAge.
Hello
I’m very interested I carrying your products in our new medspa. Would love to discuss your products and how they can meet our needs.
Thank you
Janet Beres
407-spa-blue
This is definitely a fascinating field. But I wonder what about the relationship between using growth factors and its correlation to increasing risk of cancer? The reason being isn’t cancer cell, cells that can’t turn off their growth factors?
Hi, Crystal.
Cancer cells replicate in accelerated and uncontrolled fashion because the machinery that typically prevent such runaway growth fail to perform their duties. Robert Weinberg, Ph.D., Whitehead Institute for Biomedical Research writes that “Cancer cells have learned how to grow in the absence of growth stimulatory signals that normal cells require from their environment, and they have learned how to grow in the presence of growth inhibitory signals that normally succeed in stopping the proliferation of normal cells.” The fact of the matter is all cells are exposed to cytokines and growth factors constantly. The “language” is enormously complex. Over two hundred kinds of cells and many hundreds of bio-signals means the complexity of the conversation is immense.
There is recent information, however, that seems to indicate that the bio-signal milieu created by different kinds of stem cells can impact the behavior of cancer cells in vitro, some negatively and some positively. The pro-inflammatory profile of fat stem cell produced bio-signals demonstrate negative effects upon breast, pancreatic, ovarian, and brain cancer, making them proliferate and spread more aggressively. The exact opposite was true when bone marrow stem cell bio-signals was put into cultures of certain cancer cells.
Another way to think about the relationship between growth factors and cancer is to think of it as you would nutrition. Cancers require all the same nutrients to grow that the rest of your body needs – calories, protein, vitamins, minerals. Aggressive cancers can even “steal” nutrients from other organs, resulting in cancer cachexia (malnutrition). In that same way, cancers can “steal” growth factors for their nefarious agenda. Indeed they can even steal stem cells and other trophic factors, like blood vessels. Whole organs can be purloined and made to work for the evil tumor. Just as you wouldn’t say that essential nutrients like vitamins caused the cancer just because the cancer can use them to grow, you also wouldn’t blame most growth factors from being stolen by a cancer to aid it in growing. Also, as DrGeorge alludes, there are cytokines that are inflammatory (like leptin) and these are involved in inflammation and chronic inflammation can cause cancer. In that case, there is a direct link. So, it’s important to know what cytokines or growth factors you are putting on your skin. Much of that is determined by the origin of the cell you use to extract growth factors. Now, to reassure, in the whole history of growth factors being applied to skin there has never been a reported case of a cancer being caused. In fact, we are unable to find adverse events of any sort. But it doesn’t mean we should lower our guard. We are very fussy, for instance, in which growth factors we apply in areas of the body where there might possibly be an occult cancer lurking that could go undetected. We also warn against e.g. chronically applying adipose fat derived stem cell growth factors near breasts – due to the purported link between leptin and breast cancer. We will do a whole post in the near future detailing research where stem cells and cancers overlap – it is pretty advanced stuff.
Why is there no email list!! I need updates for new GF posts! 🙂
There will be soon!
I second this, I forget about you guys until I want a true review on something and I go look up the page again, I would totally sign up for a newsletter!
Do you think a product such as neocutis is good for skin or something that restores good bacterias? I was looking at MotherDirt to restore natural biome. I heard they have no preservatives. I wonder if products such as Neocutis and SkinMedica have preservatives that counteract the ‘anti-aging’ process. Thoughts?
Jen, it’s a good idea, but is also very complex. Deep science, not completely worked out. Mother Dirt uses ammonia-oxidizing bacteria in their skin spray. These bugs produce nitrous oxide, a greenhouse gas that has 300 times the potency of CO2 in depleting ozone. “Nitrous oxide is a really nasty agent to be releasing on a global scale.” There are many probiotic, prebiotic, and postbiotic approaches to encouraging a healthy skin biome. These are not the bacteria I would choose. Some preservatives are problematic, but most are not. And because they keep your products from growing bugs of any sort while on the shelf, they serve a useful function. Some preservatives are actually natural.
I am intrigued by your research and products but have a question before I am comfortable buying them. I am healthy and in my 40’s. My daughter has a chronic kidney disease that may require a future transplant organ which I plan to provide. Will your products interfere in any way with that? I currently microneedle using 0.5 mm and would like to try your microneedling product. I know this is still pretty superficial but want to be 100% sure of its safety in this circumstance.
We understand your concern and applaud you for giving such a loving and precious gift to your daughter, hopefully an event far into the future. Several past BFT posts describe how the ingredients in our microneedling products already exist within your own skin naturally, except of course the preservative ingredients which are the same as ones used to preserve multidose vaccines, drugs, etc.
We can envision no way in which use of our products will in any way affect your suitability as a renal donor once the time comes. The molecules are naturally occurring, the rate of systemic uptake is minimal since the benefits are local in nature, and discontinuance for even a few days or so would essentially eliminate any trace of the product.
I have dry skin and love using Aquaphor or Vaseline as the final step of my skincare routine. I was curious what you think of a patient using the AnteAGE MD TGFB3 occlusive nightly, even if not after a microneedling procedure?