This is a follow up to our earlier post revealing the dangers of fat stem cells secretions as the basis of daily application cosmeceuticals. To be clear, we are not talking about fat transfers augmented by stem cells, or autologous adipose stem cell injections as used in orthopedics. Those are one time procedures, in which inflammation will occur briefly, leaving behind viable (hopefully) fat cells. What we are talking about is topically applied products based on the growth of adipose (fat) stem cells in laboratory culture, then taking those secretions and putting them in face creams and serum.
So, what’s the difference, you say? The difference is timing, or more specifically chronicity.
We do not worry about the brief episodes of inflammation occurring at a point in time, followed by a long period in which the skin (and mesenchymal stem cells traveling to skin from the bone marrow) can use its own innate reparative process to recover, including overcoming inflammation by secreting anti-inflammatory cytokines. In fact, many of the successful procedures used in clinical aesthetics (lasers, RF, microneedling) cause controlled damage (micro wounds) in order to kick off the cascade of healing. In adults, that includes some inflammation in the earliest phase. But you don’t have a procedure like that every day. You may have a series of 3, but at spaced intervals of weeks to months. So that your skin has a chance to heal – to move from inflammation rich to an inflammation free healing environment.
What we do worry about is the daily application of low level inflammatory molecules which can result in a slow, insidious burn like the embers of a fire rather than the flames. This results in what we call fibrosis. Fibrosis is like scar tissue, although it can be under the visible part of your skin. May look fine on the surface, in fact the slight edema and cellular proliferation that accompanies this may even disguise fine lines and wrinkles. But fibrosis eventually catches up with you. it is not anti-aging, it is pro-aging. In some ways it would be like having your skin lasered every day. No chance to ever catch up.
By the way, the older you get, the longer it takes to move from inflammation to anti-inflammation, no matter what the stimulus. This is why inflammation and aging are tightly bound. Eventually we cannot keep up with the minor insults of life (sun, etc). Inflammation, ultimately, is fatal.
Why do companies persist in marketing skincare products based on laboratory culture of fat stem cells? Because they’re plentiful, they’re cheap, and they’re very easy to grow. Plus, thousands of gallons of fat are available daily from middle-aged women (and some men) undergoing liposuction so the raw material is in abundant supply.
Sure, a little extra edema fluid can make fine lines less visible and the skin appear plumper, but what is the long term effect when it is well known that inflammation is pro-aging? Seems counter-productive to us in the long run – actually pro-aging. There are better choices, including our favorite – bone marrow stem cells.
But, what about those cosmetic physicians who inject autologous fat stem cells for aesthetic procedures? For starters, there’s a difference between an injection during a procedure versus a product intended for daily indefinite topical use. A little inflammation and enhanced angiogenesis (new blood vessel formation) can be of benefit during fat grafting. But even injected fat stem cells may be problematic.
We are quite certain most practitioners are not up to speed on the growing bad rap scientists are giving adipose derived stem cells. Some of the research is very new, with additional studies published frequently. The areas of most concern have to do with the role of fat and fat stem cells in the genesis and progression of certain cancers, and their well-established role in systemic inflammation, metabolic syndrome, insulin resistance and diabetes. Their profoundly pro-inflammatory behavior is not in dispute.
The studies below are just a few of the many that raise our concerns and our eyebrows. The text is adopted directly from the articles with minor deletions of super high science jargon, but you’ll get the idea. How long will it be before companies pitching the “benefits” of products made using adipose derived stem cell conditioned media are forced to address the elephant in the room.
Obesity, Inflammation, and Cancer.
Annual Review of Pathology 2016 May 23;11:421-49.
Obesity confers increased risk for multiple serious conditions, including cancer, and is increasingly recognized as a growing cause of preventable cancer risk. Chronic inflammation, a well-known mediator of cancer, is a central characteristic of obesity, leading to many of its complications, and obesity-induced inflammation confers additional cancer risk beyond obesity itself. Multiple mechanisms facilitate this strong association between cancer and obesity. Adipose tissue is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of proinflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance protumoral effects. Dysregulated metabolism that stems from obesity, including insulin resistance, hyperglycemia, and dyslipidemia, can further impact tumor growth and development.
Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates.
Tissue Engineering Part A. 2011 Jan;17(1-2):93-106
Adipose-derived stem cells (ASCs) have been proposed to stabilize autologous fat grafts for regenerative therapy, but their safety is unknown in the setting of reconstructive surgery after mastectomy. Here, we ask whether ASC promote the in vitro growth and in vivo tumorigenesis of metastatic breast cancer clinical isolates. Metastatic pleural effusion (MPE) cells were used for coculture experiments. ASC enhanced the proliferation of MPE cells in vitro (5.1-fold).
The secretome profile of ASC resembled that reported for MSC, but included adipose-associated adipsin and the hormone leptin, shown to promote breast cancer growth. Our data indicate that ASC enhance the growth of active, but not resting tumor cells. Thus, reconstructive therapy utilizing ASC-augmented whole fat should be postponed until there is no evidence of active disease.
The White Adipose Tissue Used in Lipotransfer Procedures Is a Rich Reservoir of CD34+Progenitors Able to Promote Cancer Progression
Cancer Res; 72(1); 325–34. 1 January 2012
Previous studies have suggested a “catalytic role” in neoplastic angiogenesis and cancer progression for endothelial progenitor cells (EPC). We have found that human and murine (mouse) white adipose tissue (WAT) is a very rich reservoir of EPCs with endothelial differentiation potential, containing a mean of 263 times more EPC cells/mL than bone marrow. Compared with marrow-derived cells, purified WAT-CD34+ cells expressed similar levels of stemness-related genes, significantly increased levels of angiogenesis-related genes, and increased levels of fibroblast activation protein-α, a crucial suppressor of antitumor immunity. In vitro, WAT-CD34+ cells generated mature endothelial cells and capillary tubes as efficiently as mature mesenchymal cells. The coinjection of human WAT-CD34+ cells from lipotransfer procedures contributed to tumor vascularization and significantly increased tumor growth and metastases in several orthotopic models of human breast cancer in immunodeficient mice. Endothelial cells derived from human WAT-CD34+ cells lined the lumen of cancer vessels. These data indicate that CD34+ WAT cells can promote cancer progression and metastases. Our results highlight the importance of gaining a better understanding of the role of different WAT-derived cells used in lipotransfer for breast reconstruction in patients with breast cancer.
Adipocytes contribute to the growth and progression of multiple myeloma: Unraveling obesity related differences in adipocyte signaling.
Cancer Letters 2016 Jun 16;380(1):114-121
Obesity increases the incidence and progression of multiple myeloma (MM), yet the molecular mechanisms by which adipocytes contribute to cancer development and patient prognosis have yet to be fully elucidated. Here, we obtained human adipose-derived stem cells (ASCs) from twenty-nine normal (BMI = 20-25 kg/m2), overweight (25-30 kg/m2), obese (30-35 kg/m2), or super obese (35-40 kg/m2) patients undergoing elective liposuction. Upon differentiation, adipocytes were co-cultured with RPMI-8226 and NCI-H929 MM cell lines. Adipocytes from overweight, obese and super obese patients displayed increased PPAR-gamma, cytochrome C, interleukin-6, and leptin protein levels, and decreased fatty acid synthase protein. 8226 MM cells proliferated faster and displayed increased pSTAT-3/STAT-3 signaling when cultured in adipocyte conditioned media. Further, adipocyte conditioned media from obese and super obese patients significantly increased MM cell adhesion, and conditioned media from overweight, obese and super obese patients enhanced tube formation and expression of matrix metalloproteinase-2. In summary, our data suggest that adipocytes in the MM microenvironment contribute to MM growth and progression and should be further evaluated as a possible therapeutic target.
Diabetes 2015 Jul; 64(7): 2341-2343.
Obesity fuels the development of metabolic syndrome which includes elevated glucose levels, insulin resistance, elevated blood pressure, and increased levels of triglycerides. Obesity and metabolic syndrome increase the risk of metabolic diseases, such as type 2 diabetes (T2D), cardiovascular disease, and atherosclerosis, and contribute to a reduction in life expectancy. In the U.S., the obesity rate in adults has reached 36% and obesity affects more than 1 billion people worldwide. Currently, 9.3% of the U.S. population has diabetes. In adults, T2D accounts for 90–95% of all diagnosed cases of diabetes, and the estimated total economic burden of diabetes in the U.S. is $245 billion.
Adipose tissue is a perplexingly complicated endocrine organ that contains a multitude of cell types, such as adipocyte-derived stem cells (ASCs), adipocytes, vascular cells, and immune cells, that all play a role in obesity-induced inflammation. Excess calorie intake induces adipose tissue enlargement and causes adipocyte dysfunction. Enlarged adipocytes produce cytokines and chemokines that include TNF-α and chemokine (C-C motif) ligand-2, which, in turn, promote immune cell accumulation in the adipose tissue. Immigrated inflammatory immune cells enhance adipose tissue inflammation, which further exacerbates adipocyte dysfunction. TNF-α secreted by inflammatory cells interferes with insulin receptor signaling pathways in adipocytes and causes peripheral insulin resistance.
Co-culturing human ASCs (from obese donors) with human mononuclear cells (MNCs), drastically changes the phenotype of MNCs. IL-1β and IL-6 production are both elevated in coculture experiments using ASCs and MNCs. Altogether, these results suggest that the triumvirate of monocytes, ASCs, and T cells controls adipose tissue inflammation.
Inflammasomes are caspase-1–containing multicomponent protein complexes, which proteolytically cleave IL-1β and IL-18 to induce the secretion of these cytokines by adipose tissue macrophages. Signals derived from ASCs or MNCs induce inflammasome activation and IL-1β secretion by monocytes.
Adipose Tissue–Derived Stem Cells from Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation
Diabetes 2015 Jul; 64(7): 2477-2488.
Obesity, through low-grade inflammation, can drive insulin resistance and type 2 diabetes. Herein, we cocultured human adipose-derived stem cells (ASCs) from obese individuals with MNCs and analyzed their reciprocal behavior. Presence of ASCs 1) enhanced interleukin (IL)-17A secretion by Th17 cells, 2) inhibited γ-interferon and tumor necrosis factor α secretion by Th1 cells, and3) increased monocyte-mediated IL-1β secretion. IL-17A secretion also occurred in stromal vascular fractions issued from obese but not lean individuals. Th17 polarization mostly depended on physical contacts between ASCs and MNCs—with a contribution of intracellular adhesion molecule-1—and occurred through activation of the inflammasome and phosphatidylinositol 3-kinase pathways. ASCs favored STAT3 over STAT5 transcription factor binding on STAT binding sites within the IL-17A/F gene locus. Finally, conditioned media from activated ASC-MNC cocultures inhibited adipocyte differentiation mRNA markers and impaired insulin-mediated Akt phosphorylation and lipolysis inhibition. In conclusion, we report that obese- but not lean-derived ASCs induce Th17 promotion and monocyte activation. This proinflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a proinflammatory process taking place in AT during obesity and defines novel putative therapeutic targets.