Mesenchymal Stem Cell-Derived Paracrine Products as Senotherapeutic Interventions for Skin Photoaging: A Preclinical Systematic Review of the Senescence-SASP Axis

Abstract

Chronic ultraviolet (UV) exposure induces oxidative stress, mitochondrial dysfunction, DNA damage, and cell cycle arrest through the p53/p21^CIP1^ and p16^INK4a^ pathways, contributing to cellular senescence and the development of the senescence-associated secretory phenotype (SASP). Objective: This study aimed to synthesize evidence on how mesenchymal stem cell (MSC)-derived secretomes, conditioned media, and extracellular vesicles (EVs) modulate the senescence–SASP axis in UV-induced skin photoaging and to evaluate their translational potential. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, PubMed, Scopus, and Web of Science were searched for original studies published between January 2021 and July 2026 using terms related to skin photoaging, MSC-derived secretomes, conditioned media, EVs/exosomes, cellular senescence, SASP, and senotherapeutics. Eligible studies investigated MSC-derived secretomes, conditioned media, or EVs in UV- or oxidative stress-induced skin models and reported senescence biomarkers, SASP mediators, or associated molecular pathways. Of the 211 records identified, 149 remained after duplicate removal, and 15 underwent full-text assessment, resulting in eight studies included in the qualitative synthesis. All eight studies were preclinical and employed in vitro and/or in vivo UVA/UVB exposure models. MSC sources included umbilical cord tissue, adipose tissue, and hair follicles. Two studies investigated adipose-derived MSCs subjected to hypoxic or three-dimensional culture preconditioning, while two examined engineered molecular cargo (miR-125b-5p and circ_0011129). Results: MSC-derived secretome and EV treatments consistently reduced senescence markers, oxidative stress, and DNA damage while preserving collagen and elastin. The implicated mechanisms included PINK1/Parkin-mediated mitophagy, GATA2/PZP/GRP75 signaling, the TIMP1–ADAM10–Notch1–HES1 axis, and TGF-?1/Smad signaling. However, canonical SASP mediators were evaluated in only four studies. Delivery methods also influenced treatment efficacy, with subcutaneous injection and microneedle-assisted administration demonstrating effects on dermal tissue.