DPHD from Curcuma comosa 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.