DPHD from <i>Curcuma comosa</i> Enhances the Expansion and Osteogenic Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells While Attenuating Senescence

Osteoporosis and other degenerative bone disorders are major health burdens, and current therapies are limited in restoring bone regeneration. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) offer promise for regenerative medicine, but their clinical potential is restricted by replicative senescence during ex vivo expansion. In this study, we examined the effects of (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (DPHD), a diarylheptanoid derivative from Curcuma comosa Roxb, on hUC-MSC proliferation, senescence, migration, and osteogenic differentiation. Treatment with DPHD (2.5–5 μM) enhanced cell viability and proliferation while preserving MSC-specific marker expression and stemness-related genes (NANOG, OCT4, SOX2). DPHD significantly reduced senescence-associated β-galactosidase activity and reduced the expression levels of the cell cycle regulators p16 and p21, indicating an antisenescent effect. Moreover, DPHD suppressed the secretion of cytokines associated with the Senescence-Associated Secretory Phenotype (SASP), including IL-1β, IL-6, and MCP-1, and attenuated H2O2 induced ROS accumulation, confirming its antioxidant property. Furthermore, DPHD promoted osteogenic differentiation, as shown by increased ALP activity, calcium deposition, and upregulation of osteogenic marker genes. Mechanistically, DPHD upregulated Wnt/β-catenin-associated genes during proliferation (CTNNB1, C-MYC, AXIN2, CCND1) and enhanced osteogenic gene expression during differentiation (RUNX2, ALP, COL1A1), while inhibition of Wnt/β-catenin signaling suppressed these increases. Therefore, both the proliferative and osteogenic effects of DPHD are at least partly mediated through activation of the Wnt/β-catenin pathway. Collectively, these findings suggest that DPHD enhances the expansion and osteogenic potential of hUC-MSCs by attenuating cellular senescence while preserving their functional properties, underscoring its potential as a natural compound for improving MSC-based therapies in regenerative medicine.