Scientific Papers

MiR-223–3p overexpressed adipose mesenchymal stem cell-derived exosomes promote wound healing via targeting MAPK10

Healthy skin plays a vital role in maintaining physiological homeostasis. As a protective cover against the external environment, the skin is often subject to potential damage; wound healing is therefore an important process for the survival of all living organisms (Wilkinson and Hardman, 2020). The process of wound healing is complex and usually divided into four primary stages: hemostasis, inflammation, proliferation, and dermal remodeling (Wang et al., 2018). However, many conditions can lead to poor or even nonhealing wounds, which thereby require medical intervention. For example, chronic diseases such as diabetes or peripheral vascular diseases can contribute to impaired wound healing, while acute trauma can lead to loss of skin organ function, leaving the body vulnerable to microbial infections, heat disorders, and fluid loss (Sorg et al., 2017). Although many approaches have been used to treat wounds, the current best practice for wound management is aimed at addressing chronic secondary causes and relies heavily on patient compliance, contributing to the treatment of up to 40% of chronic wounds that continue for months or years after extensive treatment (Guest et al., 2015). Therefore, there is an urgent need to develop effective therapeutic strategies for wound management.

Increasing evidence has shown that mesenchymal stem cells (MSCs), including adipose mesenchymal stem cells (AMSCs), proliferate and differentiate into skin cells to repair damaged or dead cells, thus playing a key role in skin repair and regeneration (Fu et al., 2019). A previous study reported that AMSCs activate a series of bioactive factors through autocrine and paracrine pathways, thus participating in cell regeneration and healing processes (Mazini et al., 2020). Exosomes, membranous vesicles– 50–150 nm in diameter, can be taken up by cells via autocrine or paracrine pathways and are the main contributors to stem cell efficacy (Kalluri and LeBleu, 2020). Li et al. demonstrated that AMSCs-derived exosomes could bind to gelatin sponges by polydopamine coating and be released slowly, and that the AMSCs-derived exosome-modified scaffold showed great potential for treating large bone defects (Li et al., 2023). Another study showed that the administration of AMSCs-derived exosomes in Pluronic F-127 hydrogel (PF-127) could improve the efficiency of exosome delivery and maintain the biological activity of AMSCs-derived exosomes. In vivo experiments have further shown that AMSCs-derived exosomes encapsulated in PF-127 are more effective at promoting wound healing and regeneration than administration of AMSCs-derived exosomes alone (Zhou et al., 2022). Additionally, in wounds, AMSCs-derived exosomes can promote angiogenesis, regulate inflammatory and immune responses, accelerate the proliferation and re-epithelialization of skin cells, and regulate collagen remodeling to inhibit scar hyperplasia (An et al., 2021). These reports further confirm that AMSCs-derived exosomes are promising novel factors in wound repair and regeneration.

Exosomes, which are rich in miRNAs, mRNAs, proteins, and lipids, are believed to be communication tools between cells and are promising biological gene delivery systems (Hade et al., 2021). Previous studies have shown that the primary mechanism of action of exosomes is post-transcriptional gene regulation through miRNAs, which are small endogenous RNA molecules with approximately 22 nt in length (Isaac et al., 2021). MiRNAs have crucial functions in health and disease, including cardiovascular diseases, different types of cancers, and wound healing (An et al., 2021, Zhang and Yu, 2019, Wang et al., 2021a). Li et al., 2021a, Li et al., 2021a showed that miR-17, miR-19a, miR-18a, miR-20a, and miR-19b are upregulated during wound repair, and a combination of miR-19a/b and miR-20a improves wound healing in a mouse model of type 2 diabetes by modulating the inflammatory response of keratinocytes. Another study found that AMSCs-derived exosomes carrying miR-671 directly target TGFBR2 and reduce the phosphorylation of Smad2, thereby relieving myocardial infarct-like symptoms in vivo and in vitro (Wang et al., 2021a, Wang et al., 2021a). However, the potential roles and underlying mechanisms of specific miRNAs using AMSC-derived exosomes as carriers for skin tissue wound healing remain unclear.

In this study, related expression profiles were downloaded from the NCBI Gene Expression Omnibus (GEO) database and bioinformatic analyses was performed to screen the key miRNAs closely associated with wound healing. Based on the co-expression network, miR-223–3p was the hub node and its corresponding target, MAPK10, was found to be involved in the cAMP, neurotrophin, and dopaminergic synapse pathways. This further validated the interaction between miR-223–3p and MAPK10, and the effects of AMSC-derived exosomes carrying miR-223–3p on wound healing and related potential mechanisms were investigated in vivo. These results provide new insights for the improvement and promotion of wound repair.

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