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Exosomes are emerging bioactive substances involved in multiple biologic and cellular activities of the skin. These nanosized small membrane vesicles (30-100nm) are secreted by all eucaryotic cells, including skin cells. Exosomes, once thought to be a method of expelling cellular waste, are now viewed as important intercellular communication vehicles. Exosomes contain cargo including mRNA, miRNA, proteins such as cytokines and growth factors, and lipids that originate from host cells and direct various cellular responses in target cells. To influence biologic activity, exosomes must be recognized by surface receptors, fuse to the target cell membrane and be ingested through endocytosis by the target cell.

Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory and trophic effects. They can be readily harvested from human adipose tissue and are used in fat grafting for a filler effect. Adipose-derived stem cells (ADSCs) have regenerative capabilities promoting proliferation, migration, and secretory activity of keratinocytes and fibroblasts. Recent studies have demonstrated that many of the beneficial effects of ADSCs can be obtained by using cell free extracts containing cytokines and extracellular vesicles, such as exosomes. The use of exosomes for therapeutic applications is dependent on cell culture techniques with 3-D cultures being favored. Isolation techniques, such as ultracentrifugation, ultrafiltration, and precipitation, are required to produce high quality exosomes suitable for commercial use. Exosomes are non-immunogenic and safe as topical treatments. They can also be loaded with drugs, making them valuable as drug delivery systems. Thus, exosomes have enormous potential as therapeutic and cosmetic ingredients.

Exosomes have been studied in a variety of skin conditions. Wound healing is divided into five stages: inflammatory, epithelialization, wound contraction, collagen deposition, and remodeling. Intercellular communication is essential in wound healing as it requires a coordinated effort by keratinocytes, fibroblasts, macrophages, and inflammatory cells. Exosomes from macrophages promote wound healing by stimulating angiogenesis and cell proliferation. These macrophage-derived exosomes cause conversion of M1 macrophages to M2 macrophages, resulting in enhanced fibroblast migration, collagen production, and endothelial cell tube formation. ADSC exosomes loaded in an alginate-based hydrogel that functions as a scaffolding was shown to provide continuous release of bioactive materials into the wound site in animals. This dressing promoted wound closure, collagen synthesis, and angiogenesis. In addition, exosomes may help minimize scar formation. Zhang et al. demonstrated that human MSC exosomes promoted wound healing while reducing scar widths. Enhanced wound healing in diabetic mice treated with MSC exosomes resulted from an increase in angiogenesis and upregulation of vascular endothelial growth factor (VEGF). The accelerated re-epithelialization was associated with less scar formation. These studies indicate that exosomes have promise as a cell free approach to enhance wound healing and reduce scarring.

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Dr. Farris discusses the science of exosomes.
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Skin pigmentation is a coordinated effort between melanocytes and keratinocytes. Both cell types can secrete exosomes and can take up exosomes from each other. It is known that keratinocyte-derived exosomes contain miRNA and other soluble factors that are involved in pigment modulation. Co-culture of melanocytes from human foreskin and exosomes derived from keratinocytes promotes melanocyte proliferation and tyrosinase activity. In contrast, murine keratinocyte exosomes that over-express miR-330-5p significantly decrease production of melanin and expression of tyrosinase in melanocytes. Interestingly, the miRNA profile of keratinocyte exosomes is altered by UVB exposure. Exosomes isolated from UVB-irradiated keratinocytes contained miR-3196 that increases the melanin content of human melanocytes suggesting that altered exosomes may play a role in UV-induced skin pigmentation. Further studies on the role of exosomes in the cross talk between melanocytes and keratinocytes may provide new ways to modulate pigment production.

Recent studies suggest that exosomes may be useful in alopecia. Dermal papillae cell (DPC) exosomes injected into hair follicles at different stages accelerated the onset of anagen, delayed catagen, lengthened hair shafts, and resulted in larger bulge regions in mice. 3-D cultured human DPC exosomes promoted DPCs and outer root sheath viability, increased expression of insulin-like growth factor (IGF) 1, keratinocyte growth factor, and hepatocyte growth factor. They also facilitated hair shaft elongation of cultured human hair follicles and induced anagen from telogen and prolonged anagen in mice. Accordingly, dermal papillae cell exosomes hold promise for prevention and treatment of hair loss.

Exosomes are also of interest for skin rejuvenation. Exosomes from 3-D cultured human dermal fibroblasts (HDF) were delivered by needle-free injection into the skin of photoaged nude mice. HDF exosomes increased procollagen 1 and decreased MMP-1 by down-regulating TNF-α and increasing TGF-Β. The HDF exosomes also resulted in a greater increase in dermal collagen deposition when compared to bone marrow stem cell derived exosomes. Pluripotent stem cells in culture produced exosomes that mitigated changes seen in senescent human fibroblasts. These exosomes reduced expression of beta galactosidase, MMP1, MMP 3 and restored collagen type I mRNA expression. Human ADSC exosomes injected subcutaneously into photoaged skin of rats markedly decreased epidermal thickness and increased the dermal thickness of photoaged skin in seven days. There was an increase in mRNA expression of type 1 collagen while type III collagen, MMP 1, and MMP 3 was decreased. Our knowledge of the role of exosomes in skin physiology is still in its infancy, but these studies suggest that exosomes may be the next big thing in topical skincare.

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