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.

Abstract
INTRODUCTION
MATERIALS AND METHODS
    Cell culture
    Co-culture system
    Neutralizing antibody treatment
    Apoptosis assay
    Enzyme-linked immunosorbent assay for secreted factors
    Flow cytometry and reverse transcription polymerase chain reaction
    Western blot analysis
    Statistical analysis
RESULTS
    Co-culture with adipose-derived stem cells reduces apoptosis in serum-deprivedhuman dermal fibroblasts
    Adipose-derived stem cells-derived hepatocyte growth factor mediates the suppressionof apoptosis in human dermal fibroblasts
    Human dermal fibroblasts express c-Met, the receptor for hepatocyte growth factor,and require it for anti-apoptotic response
    The PI3K/AKT pathway mediates adipose-derived stem cells-derived hepatocytegrowth factor/c-Met anti-apoptotic signaling
DISCUSSION
REFERENCES

• Dongho Kang(WINDBIO, Seoul 08375, Korea)
• Eunhee Yeon(WINDBIO, Seoul 08375, Korea)
• Jiyoung Kim(WINDBIO, Seoul 08375, Korea) Corresponding author
• Taejo Kang(YUJIN Plastic Surgery & Esthetic, Seoul 06240, Korea)
• Hyekyung Song(YUJIN Plastic Surgery & Esthetic, Seoul 06240, Korea)