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

Sung-Tai Wei,Chia-Hung Hsieh,Woei-Cherng Shyu,Jung-Ying Chiang,Hui-Chen Chen,Chia-Ching Lin,Yu-Jung Lin,Yen-Chih Huang

doi:10.1186/s13287-021-02402-w

Sung-Tai Wei, Chia-Hung Hsieh + Show 6 more

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https://doi.org/10.1186/s13287-021-02402-w

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Abstract

BackgroundThe 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.MethodsGain 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).ResultsCXCR7 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.ConclusionsCXCR7 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.

Highlights

Rheumatoid arthritis (RA) is a chronic symmetrical autoimmune disease caused by loss of immunologic selftolerance and characterized by chronic joint inflammation and destruction [1]
The histological score of arthritis ranged from 0 to 4 according to the intensity of lining layer hyperplasia, mononuclear cell infiltration, and pannus formation, as described previously [18]: 0, normal ankle joint; 1, Fig. 1 CXCR7-expressing vector (CXCR7) is upregulated in mesenchymal stem cell (MSC) during the induction of osteogenic and chondrogenic differentiation. a Cell surface co-expression of the antigens, CD44, CD73, CD90, and CD105 in MSCs. b Differentiation potential of MSCs in osteogenic, chrondrogenic, and adipogenic lineages using Alizarin red, Alcian blue, and oil red O staining, respectively
CXCR7 is upregulated in MSCs during the induction of osteogenic and chondrogenic differentiation The MSCs used in our study highly expressed CD73, CD44, CD105, and CD90 (Fig. 1a) and had the potential to differentiate along osteogenic, chondrogenic, and adipogenic lineages (Fig. 1b)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic symmetrical autoimmune disease caused by loss of immunologic selftolerance and characterized by chronic joint inflammation and destruction [1]. Significant advances in our understanding of the immune mechanisms in RA have driven the development of targeted biological therapies to block cytokines or pathogenic cells. These therapies are not curative for all RA patients, and their effectiveness is dependent on the improvement of inflammation or over-active immune response. This disadvantage has led to redirecting scientific efforts and resources towards the investigation of other therapeutic approaches. 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. 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

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