Chitosan Wound Dressings Incorporating Exosomes Derived from MicroRNA-126-Overexpressing Synovium Mesenchymal Stem Cells Provide Sustained Release of Exosomes and Heal Full-Thickness Skin Defects in a Diabetic Rat Model

Abstract

There is a need to find better strategies to promote wound healing, especially of chronic wounds, which remain a challenge. We found that synovium mesenchymal stem cells (SMSCs) have the ability to strongly promote cell proliferation of fibroblasts; however, they are ineffective at promoting angiogenesis. Using gene overexpression technology, we overexpressed microRNA‐126‐3p (miR‐126‐3p) and transferred the angiogenic ability of endothelial progenitor cells to SMSCs, promoting angiogenesis. We tested a therapeutic strategy involving controlled‐release exosomes derived from miR‐126‐3p‐overexpressing SMSCs combined with chitosan. Our in vitro results showed that exosomes derived from miR‐126‐3p‐overexpressing SMSCs (SMSC‐126‐Exos) stimulated the proliferation of human dermal fibroblasts and human dermal microvascular endothelial cells (HMEC‐1) in a dose‐dependent manner. Furthermore, SMSC‐126‐Exos also promoted migration and tube formation of HMEC‐1. Testing this system in a diabetic rat model, we found that this approach resulted in accelerated re‐epithelialization, activated angiogenesis, and promotion of collagen maturity in vivo. These data provide the first evidence of the potential of SMSC‐126‐Exos in treating cutaneous wounds and indicate that modifying the cells—for example, by gene overexpression—and using the exosomes derived from these modified cells provides a potential drug delivery system and could have infinite possibilities for future therapy. Stem Cells Translational Medicine 2017;6:736–747

Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell‐free therapy

“…Such structure could also influence EV secretion and possibly their therapeutic potential since the MSCs are known to be responsive to the environmental stimuli. Similarly, it was shown that the Avitene Ultrafoam collagen hemostat caused the BM-MSCs to release twice the number of exosomes compared to the plastic surface culture based on the protein assay [32]. Although the isolation method used in this study was precipitation with no further purification, the concept itself may be beneficial to finding a way to increase the MSC-exosome yield.…”

“…Rats with traumatic brain injury exhibited significant functional recovery, increased neurite remodelling, angiogenesis and neurogenesis after treatment with exosomes [32]. They can ameliorate liver fibrosis, exert protective effects against acute liver injury and may enhance the anti-tumour effect against hepatocellular carcinoma [18].…”

“…First, the purity of the exosomes must be established based off the isolation method. Polymeric precipitation of the exosomes would require some further purification [18,32] or the ultracentrifugation of exosomes may need some additional filtering [33]. Different isolation or purification methods can also yield heterogeneous MSC-exosomes, making it difficult to compare proteomic studies between them.…”

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

“…As for noncoding RNA, the miRNAs, which are comparatively well understood among all noncoding RNAs, have been proven to enhance the therapeutic effects of native EVs (Figure 7), provide new features, and reduce their side effects when specific miRNAs are loaded into EVs 12, 43, 115. Furthermore, in an unpublished study, we successfully packed lncRNA into EVMs and found that they could regulate the competing endogenous RNA (ceRNA) network of target cells.…”

“…However, completely natural EVs may not be sufficient to provide treatments for all kinds of disease conditions; modified EVs have therefore been developed, indicating the beginning of the era of modularized EVs. A variety of modified EVs, including EVs specifically enriched in mRNA,42 miRNA,12, 43 and small interfering RNA (siRNA),20, 44 EVs with membrane modification,45, 46 and EVs carrying small molecule drugs47 and superparamagnetic iron oxide nanoparticles48 have been developed. As the era of personalized and precision medicine continues to develop, the demands of both the targeting ability toward pathological organization combined with limited damage to normal tissues49 to minimize side effects (precision medicine) and freely assembled agents based on a patient's personalized database50, 51 to maximize therapeutic effects (personalized medicine) will continually increase.…”