What were they thinking? This makes no sense at all. | BareFacedTruth.com

What were they thinking? This makes no sense at all.

A primer on combined Fibroblast and Adipose Stem Cell Conditioned Media as a skincare ingredient.

Quick question for our BFT readers, especially those who have been keeping up with our series on cell culture derived bio-signals in skincare:

What would prompt a company to launch a product line combining the weak  bio-signals produced by fibroblasts in culture with the highly pro-inflammatory ones produced by adipose (fat) derived stem cells?

That seems illogical to BFT and the literature – some of it recent – confirms that this is a bad idea.

For the record, BFT has no quarrel with anyone taking advantage of a legitimate and legal opportunity to make money. That’s the American Dream. Your humble hosts, Drjohn and Drgeorge, have been busy these past few years doing the very same thing.

From day one, however, one of our missions has been to empower our readers with the knowledge necessary to make informed choices about how they invest their skincare dollars.

There are a number of cell culture-based products available. Before you open your wallet to buy products containing combined fibroblast and adipose derived stem cell conditioned media, you should take a few minutes to arm yourself with the science required to make an informed decision on whether or not this kind of product is for you.

A NEW GROWTH FACTOR “STORY”: MULTIPLE CELL TYPE CULTURES

The April 2014 issue of The Journal of Drugs in Dermatology made it clear that dermatologists are lining up in agreement that topical bio-signals play an important role in skincare. In a feature article, Cytokines and Growth Factors were placed at the top of the Skin Health and Beauty Pyramid – above retinoids, above alpha hydroxyl acids, above sun blocks, above everything.

This is the major reason that new growth factor and cytokine products have multiplied in number over the past couple years.

Often, their stories lack important significant details about the underlying science. We feel this is one of those instances.

NEW MEANS BETTER? DON’T BELIEVE IT.

While “better” can be crafted into seductive-sounding prose that entices the non-scientist consumer to buy, BFT advises caution. The science of a fibroblast / fat stem cell culture combination doesn’t confirm better, it confirms lack of understanding of the basic physiology of tissue healing and the negative role inflammation can and does play in that process.

Why would anyone want to apply daily skincare products that promote inflammation when it has been known for decades that inflammation actually promotes tissue aging? And what about the very well-known relationship between inflammation and the promotion of fibrosis (scarring) and hyperpigmentation?

That’s a question we continue to ask, perhaps into the cone of silence, since no one has yet given us an answer.

And, fibroblasts? The bio-signals produced by them are so paltry that the first-generation product produced using fibroblast conditioned media contains more than 93% conditioned media, which because of the protein content gives TNS an odor that some people are not fond of. Smelly gym locker, anyone?

And if it takes that amount to get any oomph, there is no room in the formulation to add other recommended actives; that means buying numerous products and maintaining a complicated skincare routine.

Let’s get to specifics.

FIBROBLASTS

 

Fibroblasts are nice enough cells and because our bodies contain enormous amounts of connective tissue, they are the second most abundant cell in the body, surpassed only by red blood cells. The job of fibroblasts is to produce collagen, elastin, reticular fibers and matrix.  When it comes to producing bio-signals, they’re weaklings; when it comes to providing structure and strength to tissues and organs, they’re bodybuilders supreme.

Compared to the stem cell we champion, the bone marrow mesenchymal stem cell, fibroblasts are very puny, indeed. The images below show the comparative output of important biosignals by fibroblasts and bone marrow mesenchymal stem cells. In the graph, the small white bars indicate 1X of these biosignals, the amount produced by fibroblasts in culture. Below that is a chart that indicates how many fold increase is produced by bone marrow mesenchymal stem cells in culture.

 

 

 

 

 

 

 

 

 

 

But that’s only part of the story. Several of the bio-signals produced by fibroblasts are pro-inflammatory e.g. TGFb1, IL-1b, IL-6, IL-33.

Furthermore, fibroblasts don’t give orders, they take them. Their orders come from the migratory bone marrow mesenchymal stem cells that patrol our tissues via the vasculature. These cells arrive at sites of injury and produce the bio-signals that instruct neighboring cells, including fibroblasts, what to do and when to do it. In skin physiology and healing, fibroblasts are following orders, not giving them.

The two articles below cover this is some detail. Rodent wound models shows significant healing with bone marrow stem cell conditioned media applied; fibroblast conditioned media did no better than media is which no cells whatsoever were grown. Puny producers of biosignals. Puny, indeed.

Mesenchymal stem cells induce dermal fibroblast responses to injury Experimental Cell Research Volume 316, Issue 1, 1 January 2010, Pages 48-54

Fibroblasts in fibrosis: novel roles and mediators          Front Parmacol. 2014;5;123 

ADIPOSE (FAT) DERIVED STEM CELLS

Fat has long been recognized as an endocrine organ, secreting a variety of bio-signals that can have negative physiologic consequences. As the amount of body fat increases, the negative effects are compounded.

The quote below is from an article entitled: Biochemistry of adipose tissue: an endocrine organ Arch Med Sci. 2013 Apr 20; 9(2): 191–200.

“[….]As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example).”

The biologic effects of these bio-signals are numerous, as demonstrated in the accompanying diagram.

 

Not surprisingly, adipose (fat) derived stem cells also have a highly pro-inflammatory cytokine profile. Hence, these are the bio-signals contained within the conditioned media when fat stem cells are cultured in the laboratory. The balance beam graphic is highly pro-inflammatory.

What does that mean for products that contain fat stem cell conditioned media? It means that the net biologic effect on the skin will be to promote inflammation, and daily use will produce a chronic inflammatory stimulus which is not anti-aging at all, but the exact opposite. Not a good idea.

HOW INFLAMMATORY STIMULATION CAN PRODUCE POSITIVE CHANGES IN SKIN APPEARANCE – FOR A WHILE.

Inflammation can be “clinical”, with all of the manifestations seen in this injured finger example. We are all familiar with that phenomenon. Inflammation can also be “subclinical”, meaning that despite the fact that some of the classic signs are not evident, inflammation is present nonetheless. Chronic smoldering internal inflammation is present in many diseases and conditions of advanced age, most notably diabetes and atherosclerosis.

You can see from the finger example above that one of the hallmarks of inflammation is edema, or swelling, called tumor in Latin. It is BFT’s strongly held conviction that the edema that is present, even with subclinical inflammation, is what gives the appearance of smoother, plumper skin with many products – the edema associated with inflammation can make fine lines disappear, for a while.

It is well proven that inflammation is pro-aging in all tissues. It is also well proved that inflammation contributes to fibrotic healing (scarring) and melanocyte stimulation, the reason that darker skin types are susceptible to post-inflammatory hyperpigmentation after any kind of injury to the skin. Does chronic subclinical inflammation of the skin sound like something desirable as an anti-aging strategy?

Not to us. Therefore the decision to produce a combination product containing conditioned media from fibroblasts and adipose derived stem cells is perplexing and irrational.

BEWARE WHAT STORIES YOU BELIEVE.

But, hey, no one ever said that skincare products have to make scientific sense; they just have to have a story that can be massaged into a marketing meme that can be parlayed into cash flow.

 Perfect examples are plant “stem cell” products which have been around for years. To the unwary, it’s easy to pass off as plausible any number of stories. Here’s just three:

• A type of Swiss apple, grown preferentially during the 1800’s because of its ability to be cellared for long periods of time without shriveling and rotting, makes it the perfect stem cell “source” to help prevent and treat wrinkles in human skin. 

• The Alpine edelweiss, which grows at high altitudes and thrives while being bombarded with increased UV exposure from the sun, is the perfect stem cell “source” for products that prevent and help repair the skin damage of sun exposure.

• Because date palms thrive in very arid and hot climates, they are the perfect “source” for stem cells that can help protect the skin from the effects of arid and hot conditions.

A bit of scientific reflection is all that is required to debunk these sales pitches as nonsense, but such products sell.

Now, admittedly, we are not talking such craziness here, fibroblast and fat stem cell culture-derived products have a much more plausible marketing story. In fact, “two-for-one” alone may entice purchasers to give it a try. But, just as two wrongs don’t make a right, two non-suitable cell types don’t make a superior skincare product. 

It’s the details of the kinds of human bio-signals produced in culture that are important. Know and understand the details. 

WHERE DO THE FIBROBLASTS AND FAT STEM CELLS COME FROM?

 

 

 

 

 

 

Were it not for their use in cell culture, the tissues sources for fibroblasts and fat stem cells would be incinerated as medical waste. Fibroblasts are typically sourced from the discarded foreskins of circumcised male infants, and fat stem cells from the fat removed from middle-age women during liposuction. Fibroblasts and fat stem cells are therefore plentiful, easy to obtain and inexpensive.

INTERESTING COMPARISONS OF FAT STEM CELLS TO BONE MARROW STEM CELLS

Stem cells have been investigated in medical research and practice for well over two decades. Recently the global number of research articles that examined the basic physiology, characteristics and clinical used of stem cells surpassed 300,000! All types and sources of stem cells have been studied, with nearly 2/3 of them focusing on bone marrow stem cells which have proved superior to all other types in many ways. One major use of stem cells in clinical practice has been in orthopedics to aid in regeneration and treatment of cartilage disorders. The graph below shows that bone marrow stem cells have received the greatest scrutiny.

Of particular interest is the fact that adipose stem cells are so much more plentiful and easier to obtain, yet bone marrow stem cells continue to be the “go to” cell in regenerative and therapeutic medical applications. This should not be surprising since this is their physiologic role throughout life – repair and regeneration of damaged tissue. The physiologic role of fat stem cells?  Make more fat; nothing more.

 

Despite being relatively much less plentiful within their tissue “niche”, which makes them more difficult to obtain, bone marrow stem cells continue to be the preferred stem cell type for medical research and therapies.

 ADDITIONAL THINGS TO PONDER ABOUT FAT STEM CELLS

 

 

 

 

 

 

 

 

Procoagulant activity of human mesenchymal stem cells

J Trauma Acute Care Surg. 2017 Jul;83(1 Suppl 1):S164-S169.

[…..] All MSC populations are not equivalent; care should be taken to select cells for clinical use that minimize potential safety problems and maximize chance of patient benefit. Adipose-derived MSCs seem more consistently pro-coagulant than BM-MSCs, presenting a potential safety concern… 

A Proinflammatory Secretome Mediates the Impaired Immunopotency of Human Mesenchymal Stromal Cells in Elderly Patients with Atherosclerosis                                           Stem Cells Translational Medicine 2017.6:1132-1140

[…..] Elderly adipose MSCs exhibited a pro-inflammatory secretome with increased levels of IL-6, IL-8, CXCL8, and MCP-1/CCL2. (BFT note: the summary is that the older the source of the fat stem cell, the more inflammatory will be its secreted biosignals. Fat stem cells in skin products are sourced from liposuction waste. The average liposuction patient in the U.S. is an overweight female in her early fifties.)

Review Article: Advances in Adipose-Derived Stem Cells Isolation, Characterization, and Application in Regenerative Tissue Engineering.                                                                       Stem Cells International, Vol 2016, article ID 3206807

[…..] ADSCs may exert unintended paracrine and endocrine effects on peripheral tissues (through) secretion of metabolically active hormones such as leptin and cytokines such as TNF-a and IL-6…Obese derived ADSCs induce a pro-inflammatory response… (BFT note: patients undergoing liposuction, the source of ADSCs commercially, are not lean but significantly overweight.)

Platelet-Derived Growth Factor BB Enhances Osteogenesis of Adipose-Derived but Not Bone Marrow-Derived Mesenchymal Stromal/Stem Cells.    Stem Cells 2015 Sep;33(9):2773-84

BM-MSCs and ASCs cultured under identical osteogenic (bone forming) conditions responded differently with ASCs producing more calcium per cell.

Comparison of autologous bone marrow and adipose tissue derived mesenchymal stem cells, and platelet rich plasma, for treating surgically induced lesions of the equine superficial digital flexor tendon.   Vet J. 2017 Jun;224:76-84.

[…..] BM-MSCs resulted in a better outcome than PRP and AT-MSCs.

 

10 Comments

  1. emil says:

    I’m using Skinceuticals C E Ferulic. Do I still need to use it if I start using AnteAge Serum? Being a male I try to use fewer products to avoid a shiny face, etc. I also use Obagi tretinoin o.1%. I would like to hear your opinion.THANKS

    • drgeorge says:

      The Skinceutical product, C E Ferulic, contains antioxidants, important in preventing damage from free radicals (reactive oxygen species) that occur from solar radiation, inflammation from any source, even the oxidation of fuel (food) within our cells mitochondria. The Obagi product contains low concentration of retinoic acid. The AnteAGE system contains a variety of antioxidants (C, E, botanicals such as Yerbe Mate) so you will no longer need C E Ferulic. It also contains retinol in the Accelerator, a molecule that an enzyme within the skin converts to retinoic acid, so you would not need the Obagi product either.

      The Accelerator contains ceramides and lipids which restore barrier function and improve skin moisturization. People who find it too “rich” for their skin sometimes use the Serum during the day and Serum / Accelerator at night. If you do decide to try our products, let us know how your skin improves – it will.

  2. Mary says:

    Thank you for this article! It breaks the issue down in an extremely comprehensible way. I’ve been trying to explain to my mother why her adipose stem cell treatment for her osteoarthritis didn’t work and now I’ve got the simple words to do that.

    And thank you for developing AnteAge products, which I guess I’ve been using for around two years now. I recently went for an Excel V treatment and the doctor kept exclaiming how great my 55 year old skin looked. I’m happy.

    • drgeorge says:

      To be clear, the issue of using fat stem cells for orthopedic injections for various “arthritis” issues is somewhat different from our concerns regarding topical application to the skin. Whereas initiating inflammation in the skin, especially for the purposes of addressing the issues that occur with aging, is counterproductive, there are instances where the injection of fat stem cells may indeed have benefit. It depends on what the orthopedic issue is. That said, the vast majority of research dealing with stem cells for tissue repair and rejuvenation utilizes bone marrow mesenchymal stem cells. Makes sense, right? Bone marrow stem cells are the cells tasked with tissue repair and rejuvenation throughout our lifespan.

      Orthopedic injection of fat stem cells usually comes with the proviso: “Well. let’s give it a try and see if it helps.” Sometimes it does, and sometimes surgery including joint replacement is required to resolve symptoms. (Drgeorge should know; he just had bilateral total hip replacements a few months ago and feels 20 years younger!!)

      Thank you for using AnteAGE products. You confirm our motto coined many years ago – “Women don’t like AnteAGE, they LOVE it!”

  3. Rimavh says:

    I am one who LOVES the AnteAgeMD line because it does very good things. A quick question. Have you heard of Alphaeon Growth Serum? Contains synthetic GFs claiming to be anti-inflammatory and more stable that human derived. A client of mine swears she hasn’t needed botox since using (GFs wouldnt do that on a 50+ year old in mere months).

    • drgeorge says:

      Another example of marketing that needs close scrutiny. Everyone is jumping on the topical growth factor bandwagon and we can’t be critical of the concept since that is the sandbox we play in. But people, be wary. The science sometimes makes perfect physiologic sense, and sometimes it stinks. This one doesn’t smell so good.

      We have long cautioned against products with single growth factors, particularly EGF. Read the post on BFT about EGF by Drjohn that goes into the subject in detail. The body doesn’t work this way – there are ALWAYS many bio-signals in play – elaborate symphonic harmonies, not single note boredom. Furthermore, the EGF in the Alphaeon product we saw on their website is hardly anti-inflammatory. Just take a look at the references that popped up with a simple Google search:

      Review Article – IL-1 and EGF regulate expression of genes important in inflammation and cancer Cytokine Volume 62, Issue 1, April 2013, Pages 22-33

      The epidermal growth factor receptor: a link between inflammation and liver cancer. Exp Biol Med (Maywood). 2009 Jul;234(7):713-25.

      Research Article – The Epidermal Growth Factor Receptor Increases Cytokine Production and Cutaneous Inflammation in Response to Ultraviolet Irradiation Dermatology
      Volume 2013 (2013)

      We’re very skeptical of the scientific rigor that goes into the professional vetting of products at Alphaeon. They were signed on to market the product BFT has written about that was based on CSC14 cells, now exposed and revealed as human embryonic stem cells. Nowhere in any marketing material was that fact made clear to unsuspecting consumers, many of whom we are sure would have ethical concerns about slathering products on their face based on human embryos. There is real science in this field. It should not just be about pitching the next “great thing” to a scientifically naive populace.

  4. Rimavh says:

    Thx DrG. In terms of synthetic vs human derived, can you share further your thoughts on that please.

    • drgeorge says:

      Your question is very apropos since some parts of the world, most notably the European Union, do not permit marketing of human cell-derived products. The prohibition goes back decades to the time of the European (primarily British) “mad cow” disease panic of the 80s and 90s. A little bit about bovine spongiform encephalopathy (“BSE”) in a moment. First, let’s look at synthetic cytokines and growth factors.

      Many bio-signals have been studied in depth, to the point of knowing their molecular structure precisely, as well as the genetic code responsible for their production. With this knowledge, it is possible to transfect, i.e. insert genetic code, into bacteria, yeast, fungi, insects, animal and plant cells, making these non-human cells capable of producing exact molecular copies of human bio-signals. This process is referred to “recombinant” synthesis. It is also possible to chemically “assemble” exact replicas of the molecule.

      The physiologic effect of most bio-signals has been studied to the point that their effects on human cells can be accurately predicted. As we have discussed elsewhere in BFT, nowhere in human physiology does a bio-signal (cytokine, growth factor, interleukin, interferon, etc.) function in isolation, but rather in combination with many other bio-signals simultaneously present. The physiologic result is their net stimulatory and inhibitory effect. For this reason, we are not advocates of skincare products that tout the use of only one or two synthetic bio-signals.

      Our opinion is synthetic bio-signals should be used in logical and rational combinations that more closely mimic how our bodies function. We have, in fact, developed a product platform based on this technology for markets where human cell derived bio-signals are not permitted. Products based on this platform may contain eight or more bio-signals, the selection of which is based on the knowledge and experience we have garnered through our work with bone marrow mesenchymal stem cells.

      In 1996, the EU banned use of human derived tissues or products in skincare. Their concern was, and continues to be, disease transmission despite the fact that searches done now of PubMed (international internet based medical and scientific search engine), Google Scholar and the FDA database fail to produce a single instance of disease transmission in this way. It is well established that prion diseases – bovine spongiform encephalopathy and human spongiform encephalopathy aka Creutzfelt-Jacob disease – are never transmitted by casual contact or topical application of products to the skin. The means of transmission are 1) genetic inheritance; 2) ingestion of infected tissue, specifically cattle brain or spinal cord; 3) tissue or organ transplantation, with four cases related to blood transfusion.

      Nonetheless, the “panic” in Europe was well justified. Data shows during the 1980s and 1990s, there were 188,652 confirmed cases of BSE worldwide, with 183,841 of these infected cattle in Great Britain. 229 people contracted a human variant of BSE through ingestion of infected cattle brain or nervous tissue, 176 of them in Great Britain. In 2008, only two patients contracted the disease, both in Great Britain.

      The ban on human cell culture derived products is related to the use of fetal bovine serum (FBS) during the cell culture process. FBS is obtained through sterile exsanguination of fetal calves during the slaughter process of pregnant cows. Cell culture techniques have been developed that do not require the use of FBS. To BFT’s knowledge, there is no record of SBE having been transmitted by FBS.

  5. sam says:

    Hey Docs,

    Do you know any practitioners in NY that are using Procell therapies? I’d like to do a treatment using the full kit ( the micro channeling device etc)

    All the best,

    Sam

    • drgeorge says:

      We suggest you contact ProCell Therapies through their website. They should have all the information you need. They have wonderful products!

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