Human bone-marrow derived mesenchymal stem cells (hBMSC) carry great therapeutic potential in oncology and regenerative medicine. PDGF D is a powerful mitogen and chemoattractant that can activate β-PDGFR expressed on hBMSCs. In this study, we investigated a role of PDGF D in hBMSC’s differentiation into osteoblasts and adipocytes. We found that PDGF D promotes hBMSCs’ differentiation into osteoblasts while inhibits their differentiation into adipocytes. These effects were mediated in part through PDGF D’s upregulation of β-actin expression and polymerization. Mechanistically, PDGF D promptly induces significant polyubiquitination of β-PDGFR mediated in part by the E3 ubiquitin ligase HUWE1. Interestingly, ubiquitination of β-PDGFR by HUWE1 delays its internalization and degradation and prolongs downstream AKT signaling. HUWE1-regulated β-PDGFR signaling is critical for PDGF D induction of osteoblast differentiation, while it is dispensable for PDGF D inhibition of adipocyte differentiation. These findings provide insights into the molecular mechanism by which PDGF D modulates hBMSC differentiation