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

Abstract

Background: 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: DPSCs 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. Results: We 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. Conclusions: Our 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.

Clinical-grade hDPSCs Suppressed the Activation of Osteoarthritic Macrophages and Attenuated Cartilaginous Damage in a Rabbit OA Model

“…Further radiographic data showed that bone regeneration in the presence of DPSC-HA/TCP was greater than that without DPSCs, which suggests that DPSCs may be a suitable factor for skeletal tissue engineering [43]. Our previous study demonstrated that transplantation of hDPSCs markedly prevented bone loss in the early phase of ovariectomy-induced osteoporosis [31]. Moreover, HGF overexpression in hDPSCs signi cantly enhanced the protective effects against bone loss in vivo.…”

“…hDPSC preparation Clinical-grade hDPSCs were obtained from Beijing SH Biotechnology (http://www.bjshbio.com/). The hDPSCs were prepared as previously described with written consent [31]. In brief, hDPSCs were isolated and cultured in a GMP-compliant facility following ISO 8 clean room standards.…”

“…In recent decades, we have been pursuing preclinical research and clinical applications of stem cell-based therapy for the treatment of severe diseases [19][20][21][22][23][24][25][26][27][28][29]. Notably, we explored the therapeutic effects of hDPSCs on several skeletal disorders, including rheumatoid arthritis, osteoporosis, and tooth loss [30][31][32]. These studies demonstrated that transfusing hDPSCs yields promising results in maintaining skeletal homeostasis.…”

The Current Status of Mesenchymal Stromal Cells: Controversies, Unresolved Issues and Some Promising Solutions to Improve Their Therapeutic Efficacy

“…On the other hand, FoxP3-expressing MSCs prevent rejection of allogeneic grafted liver, increasing the median survival time of treated mice by increasing the numbers of Treg cells and the PD-L1 expression on MSCs ( Qi et al, 2015 ). In other studies, HGF-expressing MSCs exhibited enhanced regenerative and anti-apoptotic effects in murine models of radiation-induced toxicity ( Zhang J. et al, 2014 ; Wang et al, 2015 ), and induction of early immunosuppression in mice undergoing rheumatoid arthritis ( Dong et al, 2020 ). Bcl-2 is also a robust anti-apoptotic protein, which has been overexpressed in MSCs.…”

Clinical-grade human dental pulp stem cells suppressed the activation of osteoarthritic macrophages and attenuated cartilaginous damage in a rabbit osteoarthritis model

“…However, in the current study, the suppressive effects of hDPSCs on osteoarthritic macrophages generation in the Transwell chamber system remained, which suggested that hDPSCs suppress osteoarthritic macrophages mainly by secreting soluble factors. Numerous reports have demonstrated that hDPSCs highly express HGF, and we previously found that HGF has a pivotal role in controlling the regenerative properties of hDPSCs [ 27 ]. hDPSCs exerted multifaceted benefits for treating experimental rheumatoid arthritis by secreting factors [ 42 ].…”