Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation

Abstract

Background The major barriers to mesenchymal stem cell (MSC) therapy in rheumatoid arthritis (RA) are a low extent of tissue regeneration and insufficient immunomodulation after cell transplantation. In addition, the role of C-X-C chemokine receptor type 7 (CXCR7) and its mechanism of action in MSC-mediated osteogenic or chondrogenic differentiation and immunomodulation are unclear. Methods Gain of CXCR7 function on human MSCs was carried out by lentiviral vector-mediated CXCR7 overexpression or CXCR7 agonist, TC14012. These cells were determined the role and potential mechanisms for CXCR7-regulated MSC differentiation and immunomodulation using cellular and molecular assays. The therapeutic benefits in RA were investigated in rats with collagen-induced arthritis (CIA). Results CXCR7 was upregulated in MSCs during the induction of osteogenic or chondrogenic differentiation. Blockage of CXCR7 function inhibited osteogenic or chondrogenic differentiation of MSCs whereas gain of CXCR7 function had the opposite effects. Besides, MSCs with CXCR7 gain-of-function facilitated macrophage apoptosis and regulatory T cell differentiation in a co-culture system. Gain of CXCR7 function also promoted the production of anti-inflammatory soluble factors. A gene expression profiling assay and signaling reporter assays revealed that CXCR7 could regulate several candidate genes related to the PPAR, WNT, Hedgehog or Notch pathways, and their signaling activities, which are known to control cell differentiation and immunomodulation. Finally, MSCs with CXCR7 gain-of-function significantly reduced the articular index scores, ankle circumference, radiographic scores, histologic scores, and inflammation in rats with CIA compared with control MSCs. Conclusions CXCR7 promotes the osteogenic and chondrogenic differentiation of MSCs and MSC-mediated immunomodulation by regulating several signaling pathways and anti-inflammatory soluble factors. MSCs with CXCR7 gain-of-function significantly ameliorate arthritic symptoms in a CIA model.