Interaction of mesenchymal stem cells with fibroblast-like synoviocytes via cadherin-11 promotes the angiogenesis by enhanced secretion of placental growth factor (P5113)

Abstract

Abstract Bone marrow derived mesenchymal stem cells (MSC) exist in synovium of patients with rheumatoid arthritis (RA), yet the role of MSC in RA was elusive. Placental growth factor (PlGF) was known to be increased in RA synovial fluids, and blocking of PlGF attenuated the arthritis progression in mice. Herein, we investigated the migration of MSCs by PlGF and interaction of MSC with RA fibroblast-like synoviocytes (FLS). We observed that PlGF induced the chemotaxis of MSC in a dose-dependent manner. PlGF-mediated chemotaxis was inhibited by anti-flt-1 hexapeptide (GNQWFI) and by inhibitors of PI3-kinase (LY294002) and p38 MAPK inhibitor (SB203580), respectively, but not by ERK1/2 inhibitor (PD98059). MSC exposed to PlGF elicited increased phosphorylation of Akt and p38 MAPK. FLS constitutively produced PlGF, while MSC released negligible amounts of PlGF. However, coculture with MSC significantly increased the PlGF production in FLS, and this increase was depedent on the number of added MSC. As revealed by transwell experiments, direct cell contact was required to increase the PlGF production in coculture. Cadherin-11 was expressed both in FLS and MSC, and siRNA knockdown of cadherin-11 in MSC significantly abrogated the enhanced PlGF production. These data indicate that PlGF in synovial cavity could induce the migration of MSC to synovium, and homophilic interaction of MSC with FLS by cadherin-11 contribute to the progression of synovitis by enhancing the secretion of PlGF.