Mesenchymal Stem Cell-Derived Paracrine Products as Senotherapeutic Interventions for Skin Photoageing: A Systematic Review of the Senescence-SASP Axis
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Chronic ultraviolet (UV) exposure induces oxidative stress, mitochondrial dysfunction, DNA damage and cell-cycle arrest through p53/p21^CIP1^ and p16^INK4a^ pathways, leading to cellular senescence and the senescence-associated secretory phenotype (SASP). SASP-mediated inflammation and matrix degradation contribute to progressive photoageing. MSC-derived secretome represents a potential cell-free senotherapeutic strategy targeting this axis. To synthesise evidence on how MSC-derived secretome, conditioned medium and extracellular vesicles (EVs) modulate the senescence-SASP axis in UV-induced skin photoageing and assess its translational potential. Following PRISMA 2020, PubMed, Scopus and Web of Science were used to search original studies published between January 2021-July 2026 using terms related to skin photoageing, MSC secretome, conditioned medium, EVs/exosomes, cellular senescence, SASP and senotherapeutics. Eligible studies used MSC-derived secretome, conditioned medium, or EVs in UVA-, UVB-, or combined UVA/UVB-induced cutaneous photoageing models and reported senescence biomarkers, SASP mediators, or mechanistically implicated pathways. Of 211 records identified, 149 were screened after duplicate removal and 15 underwent full-text assessment, yielding eight studies for qualitative synthesis. All eight studies were preclinical, using in vitro and/or in vivo UVA/UVB models. MSC sources included umbilical cord, adipose tissue and hair follicle, with two studies using hypoxia-or three-dimensionally preconditioned adipose MSCs; two studies used engineered cargo (miR-125b-5p; circ_0011129). Secretome/EV treatment consistently attenuated senescence markers, oxidative stress and DNA damage while preserving collagen and elastin. Mechanisms involved PINK1/Parkin-mediated mitophagy, GATA2/PZP/GRP75, TIMP1-ADAM10-Notch1-HES1 and TGF-?1/Smad signalling. Canonical SASP mediators were assessed in only four studies. Delivery route influenced efficacy, with subcutaneous and microneedle-assisted delivery showing dermal effects. Preclinical evidence supports MSC secretome/EV-mediated attenuation of UV-induced cellular senescence and upstream oxidative, mitochondrial and DNA damage pathways, converging on p16/p21/p53 signalling. Direct evidence for SASP suppression remains limited, and no included study examined paracrine senescence transmission. Effects are best characterised as senomorphic and predominantly senopreventive rather than senolytic. Clinical studies of MSC-derived products for photoageing exist outside the eligible mechanistic evidence base; however, no eligible interventional clinical study assessed senescence- or SASP-specific endpoints. Standardised senescence/SASP endpoints, human and immunocompetent models and long-term safety assessment are needed for translation.
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Copyright (c) 2026 Elizabeth Gondowardojo, Desak Made Wihandani , Maulana Setiawan
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