Adipose-derived stem cell secretome has been successfully used for treatment of various diseases, e.g., multiple sclerosis, rheumatoid arthritis, osteoarthritis, fistulae, diabetes mellitus, autoimmunity, and cardiovascular diseases, but also in skin aging, skin diseases, and wound healing. Let’s focus on the skin wound healing and aging.

Skin derived adipose mesenchymal stem cell (AMSC) secretome is a key component in the S²RM technology used by NeoGenesis in many of its skin care products. These mesenchymal stem cells are found in the hypodermis and dermis of intact, normal skin. Secretome is the complete set of molecules released by the AMSCs, the same set of molecules that the AMSCs in the skin normally release to help maintain and heal the skin. Secretome is what we call “stem cell released molecules (SRM)” at NeoGenesis. All the molecules released by the stem cell. And the “2” is present because we use the SRM from two types of skin derived stem cells, hence S²RM. So what we’re using at NeoGenesis is the complete set of all stem cell released molecules from two types of skin-derived stem cells, including the AMSCs. The other stem cell type used in the S²RM are fibroblasts derived from the skin. Fibroblasts are progenitor cells that are distinct from mesenchymal stem cells. Here’s a quick look at why this skin-identical ingredient, S²RM, is so useful in skin care. We’ll focus on the AMSC component of the S²RM. In another post, I’ll describe the many benefits of the fibroblast secretome. The approach we use at NeoGenesis is what I call, “Stem cell therapy without the cells,” a methodology that uses the many molecule types released from skin resident stem cells to renormalize the skin’s physiology.

The skin is physical barrier against physical, chemical, and biological damage. It is normally self-repairing, and protects against dehydration and thermal, pathogenic, chemical, and physical stress. Repairing physical damage in the skin is a dynamic process involving five overlapping stages of homeostasis, inflammation, proliferation, re-epithelization, and fibrosis. In clinical practice, AMSCs are usually administered as part of fractionated adipose tissue i.e., as part of enzymatically isolated stromal vascular fraction (SVF or cellular SVF), mechanically isolated SVF (tissue SVF), or as lipograft. AMSCs, as part of the full thickness skin grafts, have been used by physicians in their practices beginning in 1875 when Hungarian-born Scottish-trained surgeon John Reissberg Wolfe first developed the technique.

Let’s explore some of the mechanisms by which AMSCs exert their maintenance and repair of the skin. The mechanisms are complicated, and I’ll give you a glimpse into the many proteins and pathways that underly how AMSCs work in the skin. I’ve published on the immune modulating actions of AMSCs, and those of you interested in those aspects of AMSCs can read the paper as a free, open-access PubMed listed journal article. While the detailed pathways I write about below may not be important to those of you who are not scientists, what’s of value is to recognize the many pathways and many molecules types that are involved in maintaining and healing the skin. Products using one or a few peptides or proteins for example, will have minimal effect in bringing the skin to a healthy physiological state. In contradistinction, products that contain the many molecule types, such as S²RM, needed to maintain and heal the skin, will bring safe and efficacious results.

As part of their secretome, AMSCs secrete four key growth factors that promote re-epithelization: EGF, FGF-2, IGF-1, and TGF-β. These proteins induce the mechanisms underlying tissue repair including cell migration, proliferation, and differentiation as well as angiogenesis, extracellular matrix production, and inflammation resolution. Studies have found that co-treatment of AMSCs and AMSCs secretome increases the proliferation of dermal keratinocytes and fibroblast in the skin, and the maturation of fibroblasts through, at least partially, the upregulation of microRNA. Other studies have found that AMSC secretome prevents flap necrosis (cell death) after skin flap transplantation by increasing proliferation and secretion of IL-6. Another study found that AMSC secretome enhances skin flap recovery by reducing inflammation and apoptosis. AMSC secretome also prolongs the survival of vascularized composite allografts after transplantation by immune modulation, downregulating CD4+ T and Th1 cells and upregulating Tr1 and Treg cells. This paper exemplifies that the use of AMSCs secretome is an important new approach in reconstructive and plastic surgery. This is the all-important regulation of the immune system that is necessary for wound healing as described in my recent paper.

Key to tissue repair is the mitigation of inflammation. In addition to secreted immunomodulatory proteins by AMSCs, it is possible to modulate inflammatory pathways by microRNA in the AMSC secretome. Studies have found that AMSC secretome contains miR-21, which increases migration and proliferation of HaCaT (keratinocytes) cells by enhancing the matrix metalloproteinase 9 (MMP-9) expression in the PI3K/AKT pathway, thereby increasing wound healing. Also, miR-19b from AMSC secretome enhances wound healing by regulating the TGF-β pathway through targeting chemokine C-C motif ligand 1 (CCL1) by modulating the CCL1/TGF-β signaling axis. Delving more into these mechanistic pathways, TGF-β secreted by AMSCs has been found to act synergistically with growth differentiation factor 11 (GDF11) to reverse keratinocytes aging and trigger skin rejuvenation. Enhanced re-epithelialization, collagen remodeling, angiogenesis, and vessel maturation leading to improved wound healing were also found in diabetic mice treated with engineered AMSC secretome containing miR-21-5p. In digging deeper into these pathways, keratinocyte proliferation and migration and accelerated wound healing were induced through the Wnt/β-catenin signaling pathway in vitro, confirming earlier results where AMSC secretome was found to improve wound healing also through the Wnt/β-catenin pathway. AMSC secretome can also be used in alleviating atopic dermatitis.

Studies have found that an in vivo model of atopic dermatitis after AMSC secretome injection exhibited reduced clinical score, decreased level of inflammatory cytokines, serum IgE and blood eosinophil counts and CD86+ and CD206+ cells in skin lesions, as well as diminished infiltration of mast cells. Moreover, it has been shown that levels of inflammatory cytokines such as IL-4, IL-23, and IL-31 were reduced. Recently, Shin et al. found that not only the levels of these cytokines are reduced after AMSC secretome treatment in atopic dermatitis, but also IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP were reduced. The study also demonstrated that AMSC secretome restored expression of genes responsible for lipid metabolism, including ceramides, the cell cycle, a normal inflammatory response, as well as improving the skin barrier.

Furthermore, AMSCs and their secretome can be used in skin rejuvenation and wrinkle reduction, partly by stimulating collagen synthesis and regulating the proliferation and migration of dermal fibroblasts. You can think of wrinkles as a type of wound. Other studies have demonstrated the protective function of AMSCs secretome on dermal fibroblasts and keratinocytes against UVB-induced photoaging. They found reduced skin cellular senescence was observed in the group given AMSC secretome after UVB irradiation. Moreover, treatment with AMSCs secretome improved collagen I, collagen III, elastin, and TIMP-1 expression. AMSC secretome treatment was also able to upregulate the antioxidant response element (ARE), thus preventing and remediating damage to lipids, proteins, and DNA in the skin. 

These examples provide a glimpse into the complexity of maintaining and healing the skin, and exemplify why carefully formulated products that contain a multitude of skin-identical proteins, such as the S²RM in NeoGenesis products, are critical to providing a natural, safe, and efficacious means for skin care.