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

Abstract

Background Although increasing evidence has demonstrated that human dental pulp stem cells (hDPSCs) are efficacious for the clinical treatment of skeletal disorders, the underlying mechanisms remain incompletely understood. Osteoarthritis (OA) is one of the most common degenerative disorders in joints and is characterized by gradual and irreversible cartilaginous tissue damage. Notably, immune factors were newly identified to be closely related to OA development. In this study, we explored the modulatory effects of clinical-grade hDPSCs on osteoarthritic macrophages and their protective effects on cartilaginous tissues in OA joints. Methods The cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages were explored by phase contrast microscope, transmission electron microscopy, immunostaining, flow cytometry, quantitative polymerase chain reaction, and enzyme linked immunosorbent assay, respectively. Additionally, the factors and signaling pathways that suppressed macrophage activation by hDPSCs were determined by enzyme-linked immunosorbent assay and western-blotting. Furthermore, hDPSCs were administered to a rabbit knee OA model via intra-articular injection. Macrophage activation in vivo and cartilaginous tissue damage were also evaluated by pathological analysis. Results We found that hDPSCs markedly inhibited osteoarthritic macrophage activation in vitro. The cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages changed into less inflammatory status in the presence of hDPSCs. Mechanistically, we observed that hDPSC-derived hepatocyte growth factor and transforming growth factor β1 mediated the suppressive effects on osteoarthritic macrophages. Moreover, phosphorylation of MAPK pathway proteins contributed to osteoarthritic macrophage activation, and hDPSCs suppressed their activation by partially inactivating those pathways. Most importantly, injected hDPSCs inhibited macrophage activation in osteochondral tissues in a rabbit knee OA model in vivo. Further histological analysis showed that hDPSCs alleviated cartilaginous damage to knee joints. Conclusions In summary, our findings reveal a novel function for hDPSCs in suppressing osteoarthritic macrophages and suggest that macrophages are efficient cellular targets of hDPSCs for alleviation of cartilaginous damage in OA. Graphical abstract hDPSCs treat OA via an osteoarthritic macrophages-dependent mechanisms. hDPSCs suppress the activation of osteoarthritic macrophages in vitro and in vivo and alleviate cartilaginous lesions in OA models.

Strategies to Convert Cells into Hyaline Cartilage: Magic Spells for Adult Stem Cells

“…DPSCs have been applied in articular hyaline cartilage tissue regeneration and tissue engineering [ 189 ]. It was demonstrated that human DPSCs suppressed OA macrophage activation in a direct co-culture system in vitro and attenuated damage to the articular cartilage in a rabbit knee OA model in vivo [ 190 ]. Local injection of DPSCs in a model of rats with temporomandibular joint (TMJ) arthritis relieved hyperalgesia and synovial inflammation and attenuated cartilage matrix degradation, according to histologic staining and μCT scanning results [ 191 ].…”

Application of Dental Pulp Stem Cells for Bone and Neural Tissue Regeneration in Oral and Maxillofacial Region

“…Among MSCs, DPSCs are also known to secrete powerful immunomodulatory and anti-inflammatory cytokines such as transforming growth factor-beta (TGF- β ), interleukin-8 (IL-8), interleukin-6 (IL-6), hepatocyte growth factor (HGF), and indoleamine 2,3-dioxygenase (IDO) [ 84 , 85 ]. In fact, DPSCs have been shown to significantly inhibit the activation of osteoarthritis macrophages in vitro and to reduce cell morphology, immune phenotype, and expression of inflammatory factors [ 86 ]. DPSC suppressed the activation of osteoarthritic macrophage in osteoarthritis [ 86 ].…”

“…In fact, DPSCs have been shown to significantly inhibit the activation of osteoarthritis macrophages in vitro and to reduce cell morphology, immune phenotype, and expression of inflammatory factors [ 86 ]. DPSC suppressed the activation of osteoarthritic macrophage in osteoarthritis [ 86 ]. Also, the monocytic mobilizing protein-1 (MCP-1) and the secretory external domain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9) secreted from DPSCs promoted recovery after rat SCI [ 87 ].…”

Enhancing the function of PLGA-collagen scaffold by incorporating TGF-β1-loaded PLGA-PEG-PLGA nanoparticles for cartilage tissue engineering using human dental pulp stem cells

“…In this context, human dental pulp stem cells (hDPSCs) have been proven as an effective cell source in regenerative medicine due to their multipotential capabilities, donor accessibility, and low cost [10]. hDPSCs display the ability to differentiate into several lines and chondrocytes in particular [11].…”