Multi-omic analysis reveals Wharton’s jelly mesenchymal stem cells shift the pro-inflammatory phenotype of fibroblast subpopulation to induce skin rejuvenation

Skin aging is an increasingly serious clinical problem with limited treatment options. Wharton’s jelly mesenchymal stem cells (WJMSCs) represent a promising regenerative strategy. However, their mechanisms of action remain to be fully elucidated through integrated multi-omics approaches.

We established D-galactose-induced aging models using human dermal fibroblasts (HDFs) and nude mice. The effects of WJMSC transplantation were evaluated through functional assays, histology, bulk RNA-seq, microarray, and single-cell transcriptomics. Key pathways and cellular subpopulations were further investigated via bioinformatic integration and experimental validation.

In vitro, WJMSC conditioned medium restored cellular functions—enhancing proliferation, migration, and reducing ROS and SA-β-gal activity. Systemic administration of WJMSCs reversed skin thinning, increased collagen deposition, rebalanced collagen I/III ratios, and reduced cell senescence. Additionally, WJMSCs promoted M2 macrophage polarization, angiogenesis, and Lgr6⁺ stem cells activation. The combined analysis of bulk RNA-seq and cytokine microarrays suggested that the IL-17 signaling pathway might be one of the key pathways mediated by WJMSCs. Single-cell transcriptomics revealed that WJMSCs activated the synthesis of newly synthesized RNA. Fibroblasts have been identified as the central communication hub in the skin microenvironment, mediating extensive crosstalk among various cell types. Further analysis highlighted that pro-inflammatory fibroblasts and secretory reticular fibroblasts are key drivers of skin aging. It was also found that WJMSCs downregulated the circadian rhythm-associated gene Dbp, which is specifically abundant in pro-inflammatory fibroblasts.

Herein, we have provided comprehensive multi-omics evidence demonstrating that WJMSCs counteract skin aging through functional restoration, immunomodulation, and by altering the gene expression profiles of fibroblast subpopulations. These data have revealed potential therapeutic targets influenced by WJMSCs for remodeling fibroblast subpopulations in skin aging, and have provided new insights for precise cell-based interventions.