Effect of stem cell-derived exosome on skin ageing
Extracellular vesicles (EVs) are bilayer membrane vesicles secreted by cells, containing proteins, lipids, polysaccharides, RNA and other substances, which play a role in material transmission and communication between various cells and tissues. The subgroups of EVs were distinguished by diameter. Exosomes (20~200nm) are one of the important functional subgroups. Different exosomes have subtle differences in composition, reflecting the precision of cell control of exosome formation (Théry, Zitvogel and Amigorena, 2002). Exosomes can be secreted or endocytosed by most cells and are found in almost all body fluids, including blood, urine, saliva, cerebrospinal fluid, amniotic fluid, ascites, sweat, and menstrual blood (Cappello et al., 2017).
Studies have found that exosomes can mediate immune response, antigen presentation, cell migration, cell differentiation, tumour invasion etc (Bobrie et al., 2011). The function of exosomes depends on the type of cell from which they are derived. Among them, many kinds of stem cell-derived exosomes (SC-EXO) have been widely researched in many fields due to their characteristics of differentiation and regeneration, low immunogenicity and high survival rate after transplantation.
SC-EXO have shown surprising advantages in the regeneration and repair of multi-organ systems such as cardiovascular, liver and nerve (Lai, Chen and Lim, 2011; Lai et al., 2013), which shows the potential of SC-EXO in anti-ageing. Recently, it has been found that SC-EXO can reduce radiation damage to skin cells, maintain the skin barrier. It may also potentially help revitalise skin stem cells(Wang et al., 2020).
On the contrary, senescent cell-derived exosomes damage the skin barrier structure and transmit senescence signals to induce the ageing of surrounding cells. Study (Choi, Kil and Cho, 2020) showed that the expression of exosomes secreted from senescent human dermal fibroblasts (HDFs) increased by four times, and HDFs secretes elastin, collagen and other substances, which play an important role in maintaining skin elasticity and moisture(Cavinato and Jansen-Dürr, 2017). It suggested the possible role of senescent cell-derived exosomes in skin ageing.
At present, some progress has been made in the research of SC-EXO. However, there are still many obstacles in clinical application. In this paper, the relationship between exosomes from different sources and skin ageing is reviewed, and the potential of exosomes in the treatment of skin ageing is prospected.
Regulation of senescence by stem cell-derived exosomes
In the study (Oh et al., 2018), induced pluripotent stem cells exosomes (IPSCS-EXO) were used to treat HDFs after Ultraviolet-B (UVB) irradiation and HDFs passaged more than 30 generations in vitro. The results showed that IPSCS-EXO could promote the proliferation and migration, increase the expression of type I collagen in both HDFs, meanwhile significantly decrease the expression levels of Senescence-associated beta-galactosidase (SA-beta-Gal) and metalloproteinase (MMP) in the latter group of HDFs, while the highly expressed SA-Beta-Gal and MMP are both biomarkers for ageing.
Another study (Choi et al., 2019) showed similar results: adipose-derived mesenchymal stem cells exosomes (ADMSCs-EXO) enhanced HDFs migration capacity after UVB irradiation and significantly inhibited the overexpression of MMP-1, MMP-2, MMP-3 and MMP-9 induced by UVB irradiation, and enhanced the expression of collagen and elastin. Furthermore, tissue inhibitors of metalloproteinase-1 (TIMP-1) and transforming growth factor-beta1(TGF-β1) were significantly increased in ADMSCs-EXO pre-treated HDFs after UVB irradiation, which are important factors involved in MMP inhibition and extracellular matrix synthesis.
In addition, in the study of Kim et al., ADMSCs-EXO were found to stimulate ceramide synthesis after subcutaneous injection. Ceramide is a vital substance to increase skin cuticle hydration and maintain skin barrier and anti-ageing, a popular anti-ageing ingredient.
There are a small number of adult stem cells in skin tissues, which have the potential of multi-lineage differentiation and are the reserve power to maintain the youthful state of skin(Körbling and Estrov, 2003). Their collapse is one of the important reasons for skin ageing.
Reactive Oxygen Species
Some researchers found that the reactive oxygen species (ROS) level of ageing mesenchymal stem cells (MSCs) could be reduced when co-culture with highly purified IPSCS-EXO, further mitigate and the ageing phenotype on MSCs, which suggested that IPSCS-EXO may alleviate the ageing MSCs (Liu et al., 2019). Another study (Zhang et al., 2019) also found that embryonic stem cell exosome (ESC-EXO) could significantly restore the vitality of ageing MSCs. These experimental results can predict the positive effect of stem cell exosomes on ageing skin stem cells to a certain extent.
The role of exosomes in skin rejuvenation
The translational application of exosome rejuvenation is currently in the laboratory research stage and has not been reported in clinical application, but its huge application potential deserves attention. Exosomes, as communication materials between cells, can generally achieve better results than drugs. Compared with the cell itself, exosome has the same effect as the cell but more tremendous advantages in application: 1). Avoid the immune rejection problem associated with non-autologous cell transplantation (Bobrie et al., 2011); 2). Easier to save, there is no toxicity after long-term preservation and no loss of viability (Lee et al., 2016); 3). Economical mass production can be carried out through customised cell lines with controlled laboratory conditions(Sinden et al., 2017).
However, until today, the source, output and quality of exosomes and the technology related to the development of exosome derivative products are important reasons to limit its further development. Some new research brings hope for the clinical application of exosomes. For example, exosomes generated in three-dimensional cultured cells expressed higher levels of TIMP-1 than those generated in monolayer cultured cells, resulting in a significant decrease in the expression of MMP-1, which has a better capability for the prevention of skin ageing (Cha et al., 2018).
In summary, exosomes show great potential for clinical application in skin rejuvenation treatment, which can improve our appearance and prevent the development of skin diseases to a certain extent.
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