Song Hae Young, Lee Mi Jeong, Kim Min Young, Kim Kyung Hye, Lee Il Hwan, Shin Sang Hun, Lee Jung Sub, Kim Jae Ho
Medical Research Center for Ischemic Tissue Regeneration, the Medical Research Institute, School of Medicine, Pusan National University, Busan, Republic of Korea.
Biochim Biophys Acta. 2010 Jan;1801(1):23-30. doi: 10.1016/j.bbalip.2009.08.011. Epub 2009 Sep 3.
Migration of mesenchymal stem cells plays a key role in regeneration of injured tissues. Rheumatoid arthritis (RA) is a chronic inflammatory disease and synovial fluid (SF) reportedly contains a variety of chemotactic factors. This study was undertaken to investigate the role of SF in migration of human bone marrow-derived mesenchymal stem cells (hBMSCs) and the molecular mechanism of SF-induced cell migration. SF from RA patients greatly stimulated migration of hBMSCs and the SF-induced migration was completely abrogated by pretreatment of the cells with the lysophosphatidic acid (LPA) receptor antagonist Ki16425 and by small interfering RNA- or lentiviral small hairpin RNA-mediated silencing of endogenous LPA(1)/Edg2. Moreover, SF from RA patients contains higher concentrations of LPA and an LPA-producing enzyme autotoxin than normal SF. In addition, SF from RA patients increased the intracellular concentration of calcium through a Ki16425-sensitive mechanism and pretreatment of the cells with the calmodulin inhibitor W7 or calmodulin-dependent protein kinase II inhibitor KN93 abrogated the SF-induced cell migration. These results suggest that LPA-LPA(1) plays a key role in the migration of hBMSCs induced by SF from RA patients through LPA(1)-dependent activation of calmodulin-dependent protein kinase II.
间充质干细胞的迁移在受损组织的再生中起关键作用。类风湿性关节炎（RA）是一种慢性炎症性疾病，据报道滑膜液（SF）含有多种趋化因子。本研究旨在探讨SF在人骨髓来源的间充质干细胞（hBMSCs）迁移中的作用以及SF诱导细胞迁移的分子机制。RA患者的SF极大地刺激了hBMSCs的迁移，并且通过用溶血磷脂酸（LPA）受体拮抗剂Ki16425预处理细胞以及通过小干扰RNA或慢病毒小发夹RNA介导的内源性LPA(1)/Edg2沉默，完全消除了SF诱导的迁移。此外，RA患者的SF比正常SF含有更高浓度的LPA和一种产生LPA的酶自毒素。另外，RA患者的SF通过Ki16425敏感机制增加细胞内钙浓度，并且用钙调蛋白抑制剂W7或钙调蛋白依赖性蛋白激酶II抑制剂KN93预处理细胞消除了SF诱导的细胞迁移。这些结果表明，LPA-LPA(1)通过钙调蛋白依赖性蛋白激酶II的LPA(1)依赖性激活在RA患者的SF诱导的hBMSCs迁移中起关键作用。
