Dose-dependent biphasic effect of environmental UVA on stem cell function through PRPF40A, TGF-β1, NFATc1 signaling

Solar ultraviolet A (UVA) radiation makes up nearly 95% of the ultraviolet spectrum at the Earth's surface, forming a major environmental exposure. High-dose UVA is a well-established driver of phototoxicity and tissue degeneration; however, the impact of low-dose UVA on stem-cell homeostasis remains incompletely defined. Here, we investigated whether UVA elicits a dose-dependent biphasic response in human adipose-derived mesenchymal stem cells (AMSCs) and evaluated PRPF40A as a molecular indicator of stemness status. AMSCs were exposed to single or fractionated UVA regimens (0.05-2 J/cm²), followed by assessments of viability, migration, oxidative stress, apoptosis and senescence, stemness programs, multilineage differentiation, and secretome remodeling. In cultured human AMSCs, UVA induced a biphasic dose-response pattern. An ultra-low dose (0.05 J/cm²) enhanced viability and migratory capacity, reduced basal reactive oxygen species, preserved NANOG/SOX2/OCT4 expression, and promoted chondrogenic potential. In contrast, doses of 0.5 J/cm² or higher, particularly under cumulative exposure, induced oxidative injury, apoptosis, senescence-like changes, reduced stemness, impaired differentiation, and a pro-inflammatory senescence-associated secretory phenotype. Mechanistically, PRPF40A was inversely associated with stemness and showed dose-dependent co-regulation with TGF-β1 and NFAT-related readouts. Cyclosporine A altered PRPF40A- and TGF-β1-associated responses, supporting a provisional regulatory model linking PRPF40A, TGF-β1, and NFAT signaling under UVA stress. In vivo, HR-1 hairless mice showed minimal changes in skin appearance and stemness markers after low-dose UVA, whereas high-dose UVA caused dermal thinning and downregulation of cutaneous stemness markers, without reproducing a definitive biphasic pattern across the tested dose range. Collectively, our findings suggest that human AMSCs may exhibit a narrow in vitro threshold separating adaptive and injurious UVA responses, and identify PRPF40A as a candidate indicator of UVA-driven stemness destabilization.