Key Takeaways & Executive Findings
- •• hADSC-Exos effectively reduce UVB-induced skin photoaging by decreasing SA-β-gal-positive cells, p21 expression, ROS levels, and mtDNA common deletion in both HDFs and nude mice. • The anti-photoaging mechanism involves activation of PINK1/Parkin-mediated mitophagy, as evidenced by increased PINK1, Parkin, and LC3bII/I ratio, and decreased p62. • Silencing PINK1 via siRNA abolishes the protective effects of hADSC-Exos, confirming that PINK1/Parkin pathway is essential for their action. • These findings support hADSC-Exos as a promising non-invasive therapeutic strategy for skin rejuvenation and photoaging treatment.
Abstract
Background: Mitochondrial DNA (mtDNA) deletion and oxidative stress are key contributors to skin photoaging. Mitophagy helps mitigate oxidative stress. Human adipose-derived stem cell exosomes (hADSC-Exos) have been shown to counteract skin photoaging. This study aimed to explore the role and mechanism of hADSC-Exos in addressing skin photoaging. Methods: hADSC-Exos were isolated, and their surface markers were identified. Human dermal fibroblasts (HDFs) and nude mice were exposed to ultraviolet-B (UVB) irradiation, and treated with hADSC-Exos. Oxidative stress and photoaging were assessed through SA-β-gal staining, p21 expression, mtDNA deletion, reactive oxygen species (ROS) levels, and histological analysis. The PINK1, Parkin, LC3b, and p62 protein levels were measured to evaluate mitophagy. The PINK1 small-interfering RNA (siPINK1) was then used in HDFs to investigate the role of hADSC-Exos in mitophagy. Results: In UVB-exposed HDFs and nude mice, the number of SA-β-gal-positive cells, along with levels of p21, ROS, and mtDNA deletion, were significantly increased, but these effects were reduced by hADSC-Exos. Moreover, hADSC-Exos treatment significantly elevated PINK1 and Parkin levels, as well as the LC3bII/I ratio, while reducing p62 expression. In photoaged HDFs treated with hADSC-Exos, PINK1 knockout using siRNA decreased the LC3bII/I ratio and levels of PINK1 and Parkin, while increasing p62, ROS, and mtDNA deletion compared to the negative control (NC) group. Conclusion: hADSC-Exos can mitigate skin photoaging by promoting PINK1/Parkin-mediated mitophagy, thereby reducing mtDNA deletion and oxidative stress.
1. Introduction
Skin aging has become an increasing concern as society and the economy evolve [1]. Various factors contribute to skin aging, which can be categorized into internal and external factors. External factors include air pollution, ultraviolet (UV) radiation, lack of sleep, and smoking [2]. UV radiation, in particular, causes photoaging [3]. Repeated exposure to UV, especially UVB radiation, generates ROS, which accelerate the breakdown of collagen and elastin by upregulating matrix metalloproteinases (MMPs), leading to photoaging symptoms such as wrinkles, dryness, loss of elasticity, and pigmentation [4].
Current treatments for skin photoaging include photodynamic therapy, oral and topical drugs, and stem cell therapies [5]. Human adipose-derived stem cells (hADSCs) are a type of mesenchymal stem cell with self-renewal and multidifferentiation abilities, as well as immunomodulatory effects [6]. Exosomes are extracellular vesicles, ranging from 30 to 200 nm, formed through endocytosis, fusion, and exocytosis [7]. These vesicles are rich in nucleic acids, proteins, cytokines, and other bioactive compounds [8]. As a promising alternative to stem cells, exosomes eliminate the risk of immune rejection associated with stem cell transplants, offering an effective, non-invasive option for anti-aging therapies [9]. This has led to increasing interest in their potential for skin rejuvenation.
ROS include hydrogen peroxide (H2O2), hydroxyl radicals (-OH), and superoxide anions (O2¯) [10]. ROS are natural byproducts of oxygen metabolism. While low levels of ROS are important for cell signaling and maintaining oxygen balance, excessive ROS production can cause significant damage to biological structures, leading to DNA damage and lipid peroxidation [11, 12]. Mitochondria are cellular organelles responsible for energy production through oxidative phosphorylation [13]. They contain their own genetic material, mtDNA, which consists of 16,569 base pairs in a circular, double-stranded form [14]. The electron transport chain in mitochondria is the main source of ROS production, making mtDNA particularly vulnerable to mutations induced by oxidative stress [15]. A common mtDNA mutation is the 4977 bp deletion, known as the “common deletion,” which serves as an indicator of oxidative damage and is associated with photoaging.
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Yihao Wang, Wanxing Liao, Yiping Wang, Junlin Liao, Nian Chen, Chiyu Jia, Li Zeng (2026). Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04475-3
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Frequently Asked Questions
What are human adipose-derived stem cell exosomes (hADSC-Exos)?
hADSC-Exos are extracellular vesicles (30-200 nm) secreted by human adipose-derived stem cells. They contain bioactive molecules like nucleic acids, proteins, and cytokines, and are being explored as a cell-free therapy for skin rejuvenation and anti-aging.
How does UVB radiation cause skin photoaging?
UVB radiation generates reactive oxygen species (ROS) in skin cells, leading to oxidative stress. This upregulates matrix metalloproteinases (MMPs) that degrade collagen and elastin, resulting in wrinkles, dryness, and loss of elasticity. It also causes mitochondrial DNA (mtDNA) deletions, such as the common 4977 bp deletion.
What is the role of mitophagy in skin photoaging?
Mitophagy is a selective autophagy process that removes damaged mitochondria, thereby reducing oxidative stress and preventing the accumulation of mtDNA mutations. Enhancing mitophagy, particularly via the PINK1/Parkin pathway, can protect against UVB-induced photoaging.
How do hADSC-Exos improve skin photoaging?
hADSC-Exos promote PINK1/Parkin-mediated mitophagy in UVB-exposed dermal fibroblasts and skin, which reduces mtDNA common deletion and oxidative stress. This leads to decreased markers of photoaging, such as SA-β-gal positive cells and p21 expression.
What is the significance of the PINK1/Parkin pathway in this study?
The study demonstrates that hADSC-Exos upregulate PINK1 and Parkin, which are key regulators of mitophagy. Silencing PINK1 via siRNA abolishes the protective effects of hADSC-Exos, confirming that this pathway is essential for their anti-photoaging action.
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