Some things seem like they should be the same, but in fact are really, really different. You know, like those celebrity pictures posted online or in tabloids where you see the same famous person with and without makeup. So it is in the field of human stem cells. There are many different types of stem cells – but they don’t all have the same jobs in our bodies, and don’t look the same (biochemically and functionally). There are difference that are minor, and then there are differences that are major and fundamental to the rationale of why we employ them to make growth factors for skin rejuvenating purposes. This post is about such differences.
It’s no secret to readers here that DrJohn and DrGeorge have day jobs as stem cell researchers, both in the lab and the clinic, and have developed skincare products whose hero ingredients (human growth factors, cytokines, mRNAs,miRNAs, etc) derive from stem cells on permanent loan from bone marrow of young adult humans. Wearing physician/scientist/business hats has proved both interesting and challenging. Interesting in how so few people have even a rudimentary understanding of stem cell science; challenging in how best to educate people so they can grasp it.
Add to that more than a decade of nearly criminal misuse of the words “stem cell” in cosmetic advertising, and the mountain we have had to climb is both steep and high. After launching our company, like Apple Computer and Hewlett Packard, self-funded guys in a garage (true story), we had to be the tortoise, not the hare.
We’ve crawled, we’ve walked, and now we’re running. Our products were recently adopted for use and resale at one of America’s most prestigious hospital systems, a clinic listed year after year among America’s top 10 hospitals by CNN and US News & World Report. Educating their physicians and nurses about the differences between stem calls and the bio-signals they produce was key to landing this account.
Doctors can’t know everything, but surprisingly few know anything about bio-signals in skincare.
When our skincare products were first exhibited at a medical trade show, it was obvious that very few physicians are knowledgeable about cytokines and growth factors. Doctors know best what they do on a daily basis, and unless they are interested in learning about stem cells and bio-signals, they remain uninformed, even dermatologists and plastic surgeons. What surprised us most was the number of times we were told “you need to speak with my nurse” or “talk to my office manager” about this topic.
In the typical medical practice, prescription medications, including new drug development, are under the purview of physicians, non-prescription topical products, not nearly as much. It seems most physicians rely on their female office staff to make recommendations about what skincare products they should offer their patient clientele. That appears to be changing. As clinical evidence supporting new uses for bio-signals evolves, more physicians are paying attention.
“You say growth factors and cytokines can improve my procedure outcomes?”
Understandably, physician interest dramatically increased with the development of bio-signal products that focus on procedure outcomes. No surprise there. Aesthetic physicians make most of their money by providing procedures. Add to that the growing trend for less invasive procedures, laser resurfacing and dermal needling instead of surgical excision of tissue, and doctors seem to be all ears. Again, education is key. Seeing 40% faster post-laser healing, and dermal needling results that rival much more invasive procedures, more and more physicians are taking notice of the value of bio-signals in their aesthetic practice. Your humble BFT servants are honored to be leading the charge.
Like other things in life, not all bio-signals are created equal.
Whether within the body or in a laboratory flask, growth factors and cytokines patterns are determined by the genetic material within the cells that produce them. To intelligently employ bio-signaling molecules in one’s medical practice (or one’s home skincare regimen), there should be familiarity with the significant differences among the bio-signals patterns produced by adipose (fat) stem cells and bone marrow mesenchymal stem cells, and for completeness, fibroblasts. These are the three most commonly cultured cells used to produce growth factors and cytokines for skincare products.
Their major characteristics:
Adipose stem cells are most proficient at creating more fat cells, and at producing pro-inflammatory cytokine patterns. In that regard, they are like fat cells throughout the body, especially those within fat deposits in the mesentery and omentum of the abdominal cavity. Fat is known to be an inflammatory “organ”, continuously secreting pro-inflammatory bio-signals. Inflammation is well established as a pro-aging in all tissues, particularly the skin.
Fibroblasts are the source of collagen, elastin, and matrix (glycosaminoglycans and proteoglycans, including hyaluronic acid.) They are the major population of cells within the dermis and very easy to culture. They represent the first generation of cell cultures for skincare but in fact are a very poor choice if the objective is to produce growth factors and cytokines. In healing, they are the corporals, taking their orders to proliferate and produce collagen, elastin, and matrix from the commanders-in-chief of healing, bone marrow mesenchymal stem cells. Fibroblasts are extremely poor producers of bio-signals.
Bone marrow stem cells are the cells in charge of healing in all tissues, not just the skin. Their role in healing was first thought to be a result of their ability to differentiate into other cell types e.g. muscle, bone, cartilage, nerve, etc. We now know that cellular differentiation is only a small part of the role they play. Their other, much more important role, is to act as smart local “drugstores”, secreting the growth factors and cytokines that influence the behavior of nearby cells. Far from stationary within the bone marrow, they migrate into the blood stream where they gain access to the entire body. Radioactive tagging in animal models demonstrates that these remarkable cells can participate in healing, then return to the bone marrow to later again be called to duty.
As discussed elsewhere on BFT, aging skin results from decades of accumulated micro-injuries, and from chronic smoldering inflammation, which is actually a major contributor to aging in all tissues. Our work focuses on bone marrow stem cells because of their preeminent physiologic role in subduing inflammation and as command and control of tissue healing throughout the body.
Graphics clarify the difference.
Note the first bio-signal pattern below, the growth factor/cytokine pattern produced by bone marrow mesenchymal stem cells. It is highly ANTI-inflammatory. Contrast it with the next image, the highly PRO-inflammatory pattern obtained from cultures of adipose (fat) stem cells.
If one agrees that inflammation, especially chronic inflammation, is pro-aging, it seems prudent to us to apply topical products that contain anti-inflammatory bio-signal patterns, particularly if one is adopting a product as part of a daily skincare regimen. While not our choice for daily skincare, we do see possible value for the pro-inflammatory output of adipose stem cells for specific episodic applications. We are investigating one particular indication and will report our findings.
Below is a comparative graph of important growth factors and cytokines produced by cultures of fibroblasts (white bars) vs bone marrow stem cells (blue bars.) The dramatic difference is obvious; bone marrow stem cells produce many, many times the concentration of bio-signals as is produced by fibroblasts. The degree of greater production can be seen in the table below the graph.
“All stem cells are definitely not created equal.” Peer reviewed research into fat and bone marrow stem cells demonstrates the dramatically different effects their bio-signal patterns have on physiology and cellular behavior. Some of the summaries below are from abstracts published only a few months ago.
The obesity cancer paradigm: exploration of the interactions and crosstalk with adipose stem cells Stem Cells 02/2015
The increased morbidity and mortality of obesity-associated cancers have been attributed to higher levels of hormones, adipokines, and cytokines secreted by the adipose tissue. The increased amount of adipose tissue also results in higher numbers of adipose stromal/stem cells (ASCs). These ASCs have been shown to impact cancer progression directly through several mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma.
Adipose derived stem cell isolated from omentum: A novel source of chemokines for ovarian cancer growth Journal of Cancer Research and Therapeutics 01/2014
Omental adipose tissue may play crucial roles for tumor promotion through the expression of tumor promoting chemokines. Accordingly, tumor surrounding adipose tissue may be a novel target for immunotherapy of cancer.
Mammary Adipose Derived Stem Cells In BRCA-Related Breast Cancers Plastic and Reconstructive Surgery 05/2015
…adipose stem cells (ASCs) are further implicated in their secretion of harmful, pro-inflammatory cytokines to contribute negatively to the local tumor micro-environment. [….] Aggressive epithelial breast cancers are dependent on the local stromal environment that creates a favorable field for tumor growth and invasion, including a chronic pro-inflammatory cytokine profile.
Breast cancer: Adipose tissue, a bulky neighbor causing trouble BioMed Central 05/2015
We now know the fat reservoir has very active functions: it produces and secretes many biomolecules such as hormones, growth factors and pro-inflammatory cytokines, molecules named adipokines. Numerous studies have shown that adipocytes and their progenitors promote breast cancer aggressiveness by stimulating proliferation and, especially, invasion by secreting proteases and pro-inflammatory cytokines.
Human omental-derived adipose stem cells increase ovarian cancer proliferation, migration, and chemoresistance Plos One 12/2013
Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. [….]ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro.
Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion Brazilian Journal of Medical and Biological Research Sept 2013
To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were co-cultured with pancreatic cancer cells. [….] conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells.
Bone marrow mesenchymal stem cells suppress metastatic tumor development in mouse by modulating immune system. Stem Cell Res Ther. Mar 2015
Our results demonstrated that BMSCs treatment caused a delayed tumor growth and a prolonged survival in both tumor models. […] in vivo and in vitro results showed that BMSCs have a systemic suppressive effect
Paracrine effects of mesenchymal stem cells induce senescence and differentiation of glioblastoma stem-like cells. Cell Transplant 2015 March
Glioblastoma multiforme (GBM) displays high resistance to radiation and chemotherapy […] possible anti-tumor effects of the secreted factors from human MSCs on four GBM cell lines was examined. […] Conditioned media from bone marrow and umbilical cord-derived MSCs (MSC-CM) was found to mediate GBM cell cycle arrest. […]Findings support the notion that BM-MSCs posses an intrinsic ability to inhibit cell cycle and induce senescence and differentiation of GBM cell lines.
A comparison of adipose and bone marrow-derived mesenchymal stem cell secreted factors in the treatment of systemic inflammation Journal of Inflammation Nov 2011
Conditioned media from adipose and bone marrow stem cell cultures was injected into animals with septic shock and systemic inflammation. The bone marrow stem cell condition media counteracted the inflammatory cytokines, resulting in improved animal survival. Adipose stem cell condition media increased the inflammatory state, resulted in worsening of the animals’ condition and more deaths.