Pulp stem cells with hepatocyte growth factor overexpression exhibit dual effects in rheumatoid arthritis

Xiwen Dong,Shiyun Dai,Fengjun Xiao,Hua Wang,Chu-Tse Wu,Fanxuan Kong,Chao Liu,Huan Zhang,Yuning Zhang

doi:10.1186/s13287-020-01747-y

Abstract

BackgroundTo investigate the therapeutic effect of human dental pulp stem cells (DPSCs) transfected with adenovirus expressing hepatocyte growth factor (HGF) in a mouse model of collagen-induced arthritis (CIA).MethodsDPSCs were modified with Ad-HGF to produce HGF-overexpressing DPSCs, DPSCs-HGF. In experimental mouse CIA model, DPSCs-HGF and DPSCs-Null (modified with Ad-Null) were engrafted via intravenously after disease onset, which was determined by the presence of joint swelling. The therapeutic effects on joints were evaluated at 49 days after collagen injection by histopathological analysis and microcomputed tomography imaging. The inflammatory cytokines were analyzed both in sera and joints via MILLIPLEX kit and immunohistochemical staining, respectively, and the regulatory T cells (Tregs) were analyzed in peripheral blood by using flow cytometry. Furthermore, primary fibroblast-like synoviocytes were isolated, colony formation analysis and FACS were performed to evaluate the effect of HGF on the proliferation and cell cycle of FLSs. Western blot assay was carried out to clarify the signal pathway of HGF-cMet.ResultsWe found that without HGF modification, DPSC transfusion was helpful in controlling autoimmune status, local synovitis, and bone erosion after intravenous administration. However, HGF-modified DPSCs have dual role in rheumatoid arthritis (RA). In the early phase, HGF overexpression inhibited RA progression by its immunosuppressive effects, while in the late phase, HGF promoted synovitis by activating fibroblast-like synoviocytes to produce pathogenic IL-6, accelerating cell proliferation and inducing apoptosis resistance via phosphorylating the c-Met/Akt pathway. The overall effect of HGF modification attenuated the therapeutic effect of DPSCs.ConclusionsOur study provides a comprehensive evaluation of the therapeutic effect of DPSCs in the mouse model and a primary answer to the divergence of whether HGF is harmful or helpful in RA.

Highlights

rheumatoid arthritis (RA) is one of the most prevalent chronic autoimmune diseases, with an incidence of 0.5–1% in adults worldwide [1]
We demonstrated the therapeutic effect of dental pulp stem cells (DPSCs) transfusion in RA and revealed the dual effects of hepatocyte growth factor (HGF) in RA pathogenesis, all of which represent new insights as well as a novel strategy for RA treatment
The collagen-induced arthritis (CIA) model was established by two rounds of immunization on days 0 and 14 with Complete Freund’s adjuvant (CFA) + Type II collagen (CII) and Incomplete Freund’s adjuvant (IFA) + CII, respectively

Summary

Introduction

RA is one of the most prevalent chronic autoimmune diseases, with an incidence of 0.5–1% in adults worldwide [1]. RA patients have both articular symptoms (pain, stiffness, swelling, etc.) and extra-articular manifestations (pleurisy, hydrothorax, anemia, etc.) as a result of autoimmune activation, prolonged inflammation, cartilage deterioration, and bone destruction [2]. Innate and adaptive immune cells as well as synovial cells participate in RA pathogenesis [3, 4]. Adaptive immune cells (such as T or B lymphocytes) are activated, causing transformation of synovial cells to a more aggressive phenotype, which contributes to joint damage, and enhancing osteoclast activity, which induces osteolysis [3]. A promising strategy is to restore prolonged immune tolerance and to protect against local joint damage [6]. To investigate the therapeutic effect of human dental pulp stem cells (DPSCs) transfected with adenovirus expressing hepatocyte growth factor (HGF) in a mouse model of collagen-induced arthritis (CIA)

Methods

Results

Discussion

Conclusion