Bailey Keith

Background: Diabetes mellitus is a common metabolic disease that is characterized by absent or malfunctioning insulin receptors resulting in hyperglycemia. This disease affects such a large group of our population presently and the diabetes prevalence rate is predicted to rise to an even higher 7.7% (439 million people) by 2030.¹ The hyperglycemic environment causing vascular damage and other complications due to the disease impair wound healing in 10-25% of these patients. These complications cause recurrent chronic wounds and diabetic foot ulcers (DFU) that become a long term medical burden.¹ Exosomes are extracellular vesicles that are secreted from many different types of cells and are involved in intercellular signaling. In the application for diabetic wound healing they are involved in enhancing the functional cells present in the body during trauma including fibroblasts, keratinocytes, macrophages and others. They have been shown to promote collagen synthesis and angiogenesis.¹  Additionally, other pathways have been investigated including the WNT/beta-catenin pathway² and release of anti-inflammatory growth factors.

Objective: In this review, I explored the numerous inflammatory processes that stem cell exosomes intercept and affect.

Search Methods: An online search in the PubMed database for articles from 2017 to 2023 using the following keywords: “diabetes mellitus”, “stem cell exosomes”, “wound healing”

Results: Across multiple studies, stem cell exosomes continue to perform in all the ways that are being investigated including increased angiogenesis, release of anti-inflammatory growth factors, increased collagen synthesis, and direct involvement in anti-inflammatory pathways like the WNT2b/beta-catenin pathway. The scaffolds like PF-127 and FHE hydrogels have been successful in keeping the exosomes working in the hypoxic and hyperglycemic environments of a diabetic wound. The ADMSC-Exo category was the highest performing in both AOD for WNT2b and dark-staining fibroblasts while the exosomes plus inhibitor group was the lowest. The results reflected the capacity of the inhibitor and for exosomes to bring in more fibroblasts and increase percentage of collagen deposit relative to the other trials for more efficient wound healing.² The combination of exosomes and PF-127 hydrogel had the fastest wound closure rate, increased expression of both VEGF and TGF-beta, and formation of new blood vessels.¹ Complexed hydrogels also allowed for a decrease in healing time, decrease in ratio of Col-I to Col-III, and increased synthesis of Col-I and Col-III.³ There has also been success in the treatment of atrophic acne scars on human faces with no safety concerns noted.⁵

Conclusions: The prevalence of diabetes mellitus is increasing every year along with the cost of chronic healthcare conditions. The use of exosomes is proving to be a realistic option for an efficient treatment when combined with a biological scaffold to allow for the long term use that diabetic patients need.³ They have been shown to improve angiogenesis, increase anti-inflammatory growth factors and stimulate both type I and III collagen production.³ The combination of all of these anti-inflammatory processes could be a major turning point in diabetic wound healing treatment and skin regeneration.

Works Cited:

1. Yang J, Chen Z, Pan D, Li H, Shen J. Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomes Combined Pluronic F127 Hydrogel Promote Chronic Diabetic Wound Healing and Complete Skin Regeneration. Int J Nanomedicine. 2020;15:5911-5926. Published 2020 Aug 11. doi:10.2147/IJN.S249129
2. Li C, An Y, Sun Y, Yang F, Xu Q, Wang Z. Adipose Mesenchymal Stem Cell-Derived Exosomes Promote Wound Healing Through the WNT/β-catenin Signaling Pathway in Dermal Fibroblasts. Stem Cell Rev Rep. 2022;18(6):2059-2073. doi:10.1007/s12015-022-10378-0
3. Wang C, Wang M, Xu T, et al. Engineering Bioactive Self-Healing Antibacterial Exosomes Hydrogel for Promoting Chronic Diabetic Wound Healing and Complete Skin Regeneration [published correction appears in Theranostics. 2021 Nov 10;11(20):10174-10175]. Theranostics. 2019;9(1):65-76. Published 2019 Jan 1. doi:10.7150/thno.29766
4. Zhou Y, Zhang XL, Lu ST, et al. Human adipose-derived mesenchymal stem cells-derived exosomes encapsulated in pluronic F127 hydrogel promote wound healing and regeneration. Stem Cell Res Ther. 2022;13(1):407. Published 2022 Aug 8. doi:10.1186/s13287-022-02980-3
5. Kwon HH, Yang SH, Lee J, et al. Combination Treatment with Human Adipose Tissue Stem Cell-derived Exosomes and Fractional CO2 Laser for Acne Scars: A 12-week Prospective, Double-blind, Randomized, Split-face Study. Acta Derm Venereol. 2020;100(18):adv00310. doi:10.2340/00015555-3666