Human mesenchymal stem cells (hMSCs) remodel or regenerate various tissues through several mechanisms. Here, we identified the hMSC-secreted protein SCRG1 and its receptor BST1 as a positive regulator of self-renewal, migration, and osteogenic differentiation. SCRG1 and BST1 gene expression decreased during osteogenic differentiation of hMSCs. Intriguingly, SCRG1 maintained stem cell marker expression (Oct-4 and CD271/LNGFR) and the potentials of self-renewal, migration, and osteogenic differentiation, even at high passage numbers. Thus, the novel SCRG1/BST1 axis determines the fate of hMSCs by regulating their kinetic and differentiation potentials. Our findings provide a new perspective on methods for ex vivo expansion of hMSCs that maintain native stem cell potentials for bone-forming cell therapy.

Cell-cell adhesions induce various intracellular signals through hierarchical and synergistic molecular interactions. Recently, we demonstrated that a high cell density induces the expression of vascular cell adhesion molecule-1 (VCAM-1) through the nuclear factor-κB (NF-κB) pathway in human bone marrow-derived mesenchymal stem cells (MSCs). However, the specific molecules that activated the NF-κB pathway were not determined. In the present study, in experiments with receptor tyrosine kinase inhibitors, VCAM-1 expression was completely suppressed by platelet-derived growth factor (PDGF) receptor (PDGFR) inhibitors. In addition, VCAM-1 expression was significantly suppressed by knockdown with PDGFRβ siRNA, but not with PDGFRα siRNA. However, VCAM-1 expression did not increase following treatment with PDGF. The overexpression of N-cadherin, a structural molecule in adherence junctions in MSCs, promoted VCAM-1 expression and induced the marked phosphorylation of the intracellular signaling factor, Src. In addition, VCAM-1 expression and Src phosphorylation were reduced by the overexpression of a dominant negative mutant of N-cadherin. These results suggest that cell-cell adhesion, through N-cadherin, enhances the expression of VCAM-1 via PDGFRβ and the activation of Src in a ligand-independent manner in MSCs.