Circ_0011129 Encapsulated by the Small Extracellular Vesicles Derived from Human Stem Cells Ameliorate Skin Photoaging

Abstract

Photoaging is not only the main cause of skin aging caused by exogenous factors, it is also related to a variety of skin diseases and even malignant tumors. Excessive and repeated exposure to ultraviolet radiation, especially UVA induces oxidative stress, DNA damage, inflammation, and collagen and elastin degeneration, ultimately leads to skin photoaging, manifested by skin redness, coarse wrinkles, and pigmentation even skin cancer. There has been a large demand of effective prevention and medications but approaches in the current management of photoaging are very limited. In the previous study, we found that a non-coding circular RNA circ_0011129 acts as a miR-6732-5p adsorption sponge to inhibit the reduction of type I collagen and the denaturation and accumulation of elastin in UVA-induced HDF cells photoaging model. However, in vivo instability and efficient delivery to the target cell of circRNA is a major challenge for its clinical application. Therefore, improving its stability and delivery efficiency are desired. In this study, we proposed a strategy of delivering circ_0011129 with small extracellular vesicles (sEVs) from human adipose-derived stem cells (hADSCs) to intervene in the photoaging process. The results showed that sEVs from hADSCs in 3D bioreactor culture (3D-sEVs) can prevent photoaging. Consequently, by overexpressing circ_0011129 in hADSCs, we successfully loaded it into 3D-sEVs (3D-circ-sEVs) and its protective effect was better. Our studies provide a novel approach to preventing skin photoaging, which has important clinical significance and application value for the development of non-coding RNA drugs to treat skin photoaging. We first screened out hADSCs-derived sEVs with excellent anti-oxidant effects. We then compared the sEVs collected from traditional 2D culture with 3D bioreactor culture. By miRNA-seq and GEO data analysis, we found that miRNAs in 3D-sEVs were enriched in cell activities related to apoptosis, cellular senescence, and inflammation. Subsequently, we prepared circ_0011129-loaded 3D-sEVs (3D-circ-sEVs) by overexpressing it in hADSCs for the treatment of photoaging in vitro. We proved that 3D-circ-sEVs can interfere with the process of cell photoaging and protect cells from UVA radiation damage, as well as in a H2O2-induced oxidative stress model.

Exosomes in skin photoaging: biological functions and therapeutic opportunity

“…Exosomes stimulate collagen production in photoaged skin and reduce the appearance of pigmentation [4]. Moreover, photoaging is associated with a greater risk of malignant tumors like melanoma [109]. Thus, treatment of skin photoaging has important clinical significance and exosome-based therapy could be a helpful method not only in cosmetic application but also in skin cancer prevention.…”

Extracellular vesicles derived from mesenchymal stem cells: the wine in Hebe's hands to treat skin aging

“…UV radiation can induce the mitochondria-dependent generation of ROS, which can inflict oxidative damage upon DNA bases [ 125 ]. ROS, including superoxide anions, hydroxyl radicals, and H 2 O 2 , serve as essential players in cell signaling and the maintenance of cellular homeostasis.…”

“…Zhang et al . [ 125 ] found that circ_0011129, a non-coding circular RNA, functions as a miR-6732-5p adsorption sponge, thereby impeding the degradation of type I collagen and the aggregation of elastin in a UVA-induced photoaging model of human dermal fibroblast cells. To improve the in vivo stability and delivery efficiency of circRNAs, the authors prepared extracellular vesicles loaded with circ_0011129 (3D-circc-sEV) by overexpressing circ_0011129 in ADSCs and culturing them in a 3D bioreactor.…”

Progress in the Development of Stem Cell-Derived Cell-Free Therapies for Skin Aging

“…3 More advantageous in their biological function due to their small size, great stability, low cytotoxicity, immunogenicity, and target specificity (especially exosomes). 35 Limitations Products are highly heterogeneous due to the difficulty of purifying the specific therapeutic components. 54 Technical challenges in isolation and purification.…”

“…60 When observed through an electron microscope, exosomes have a typical "disk-like" structure and flat spherical shape. 35,36 EVs develop from larger intracellular vesicles known as multivesicular bodies (MVBs). MVBs are intraluminal vesicles (ILVs) formed by endosomal membrane internal budding.…”