Abstract
Stem cells secrete numerous paracrine factors, such as cytokines, growth factors, and extracellular vesicles. As a kind of extracellular vesicle (EV), exosomes produced in the endosomal compartment of eukaryotic cells have recently emerged as a biomedical material for regenerative medicine, because they contain many valuable contents that are derived from the host cells, and can stably deliver those contents to other recipient cells. Although we have previously demonstrated the beneficial effects of human induced potent stem cell-derived exosomes (iPSC-Exo) on the aging of skin fibroblasts, low production yield has remained an obstacle for clinical applications. In this study, we generated cell-engineered nanovesicles (CENVs) by serial extrusion of human iPSCs through membrane filters with diminishing pore sizes, and explored whether the iPSC-CENV ameliorates physiological alterations of human dermal fibroblasts (HDFs) that occur by natural senescence. The iPSC-CENV exhibited similar characteristics to the iPSC-Exo, while the production yield was drastically increased compared to that of iPSC-derived EVs, including exosomes. The proliferation and migration of both young and senescent HDFs were stimulated by the treatment with iPSC-CENVs. In addition, it was revealed that the iPSC-CNEV restored senescence-related alterations of gene expression. Treatment with iPSC-CENVs significantly reduced the activity of senescence-associated-β-galactosidase (SA-β-Gal) in senescent HDFs, as well as suppressing the elevated expression of p53 and p21, key factors involved in cell cycle arrest, apoptosis, and cellular senescence signaling pathways. Taken together, these results suggest that iPSC-CENV could provide an excellent alternative to iPSC-exo, and be exploited as a resource for the treatment of signs of skin aging.
Highlights
Skin aging is caused by intrinsic and extrinsic factors
Cellular senescence plays a crucial role in preventing the propagation of genetically damaged and potentially oncogenic cells in young organisms, the increase in senescent cell population leads to the decline in cell replacement system for the regeneration of damaged tissues, because stem or progenitor cells start to lose their regenerative potential with aging [16,17,18]
The extracellular vesicle (EV) exhibited a size distribution that is similar to the induced pluripotent stem cell (iPSC)-EVs of our present study rather than the iPSC-Exo. These results suggest that there is no significant difference in the beneficial effects of the iPSC-EVs on senescent cells compared to those of iPSC-Exo, and as a result, iIPnSt.CJ.-MEVol.sSccia. n20b19e, 2u0s,exdFOaRs aPEcEoRnRtrEoVlIEfoWr comparison with iPSC-cell-engineered nanovesicles (CENVs)
Summary
Skin aging is caused by intrinsic and extrinsic factors. Intrinsic aging is that involved in natural aging and age-dependence, while extrinsic aging is that caused by environmental factors, such as sunlight, and active oxygen [1]. Several age-related alterations in fibroblasts have been reported: loss of protein homeostasis [6], down-regulation of ECM synthesis [7], and up-regulation of the expression of matrix-degrading enzymes, such as collagenase, hyaluronidase, and elastase [8]; decline in respiratory capacity and imbalanced reactive oxygen species (ROS) level by mitochondrial dysfunction [9], and DNA damage at chromosomal telomeres [10] Cellular senescence is another hallmark of dermal fibroblasts in aging skin [11,12], and can be defined as irreversible cell cycle arrest activated via signaling pathways involving tumor suppressor p53, p21, and p16INK4a [13,14,15]. The improvements of physiological alterations in senescent HDFs were evaluated using quantitative measurements of protein and genes involved in senescence
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