Human dermal fibroblasts (HDFs) play a critical role in maintaining skin integrity and promoting tissue repair, but are highly susceptible to apoptosis under stress conditions such as nutrient deprivation. Adipose-derived stem cells (ADSCs) have emerged as a promising therapeutic option due to their regenerative potential and ability to secrete bioactive factors. In this study, we investigated the effect of ADSC-derived paracrine signaling on apoptosis in HDFs and explored the underlying molecular mechanisms. Using a Transwell co-culture system, we found that ADSCs significantly reduced apoptosis in HDFs subjected to low-serum stress, as confirmed by APOPercentage™ staining and the expression of apoptosis-related proteins. Among several soluble factors secreted by ADSCs, hepatocyte growth factor (HGF) exhibited the most pronounced time-dependent increase in culture supernatants. The anti- apoptotic effect of ADSCs was abolished by neutralizing antibodies against HGF, indicating a key role of this factor in mediating fibroblast survival. Further, HDFs were found to express the HGF receptor c-Met at both the mRNA and protein levels. Inhibition of c-Met signaling reversed the cytoprotective effect of ADSCs, suggesting that HGF functions through this receptor. Mechanistically, only the PI3K/AKT pathway—among the major survival pathways tested—was selectively activated in HDFs by ADSC co-culture. Pharmacological inhibition of PI3K/AKT signaling using LY294002 abolished the protective effect, while inhibition of ERK or p38 MAPK had no significant impact. These findings demonstrate that ADSC-derived HGF protects HDFs from stress-induced apoptosis primarily through activation of the c-Met–PI3K/ AKT pathway. This mechanistic insight may provide a basis for the development of stem cell– based therapies aimed at enhancing skin regeneration and fibroblast viability in degenerative or wound-healing contexts.

Streptococcus mutans (S. mutans) is a facultative anaerobic bacterium mainly found in the oral cavity and is known to contribute to tooth decay and gingivitis. Recent studies on intestinal microbiota have revealed that microorganisms forming a biofilm play important roles in maintaining tissue homeostasis through their own metabolism. However, the physiological roles of oral microorganisms such as S. mutans are still unclear. In our current study, we identified that constituents released from S. mutans (CR) reduce arecoline- mediated cytotoxicity without producing toxic effects themselves. Arecoline, as a major alkaloid of areca nut, is known to mediate cytotoxicity on oral epithelial cells and induces a sustained intracellular Ca2+ ([Ca2+]i) increase that is cytotoxic. The exposure of human gingival fibroblast (HGF) cells to CR not only inhibited the sustained [Ca2+]i increase but also the initial [Ca2+]i elevation. In contrast, CR had no effects on the gene regulation mediated by arecoline. These results demonstrate that S. mutans has physiological role in reducing cytotoxicity in HGF cells and may be considered a novel pharmaceutical candidate.