The Secretome Derived From 3D-Cultured Umbilical Cord Tissue MSCs Counteracts Manifestations Typifying Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disorder whose treatment is mostly restricted to pain and symptom management and to the delay of joint destruction. Mesenchymal stem/stromal cells from the umbilical cord tissue (UC-MSCs) have previously been proven to be immunomodulatory and more efficient than bone marrow-derived MSCs in causing remission of local and systemic arthritic manifestations in vivo. Given the paracrine nature of UC-MSC activity, their application as active substances can be replaced by their secretome, thus avoiding allogeneic rejection and safety issues related to unwanted grafting. In this work, we aimed at demonstrating the viability of applying the 3D-primed UC-MSC secretome for the amelioration of arthritic signs. A proteomic analysis was performed to both, media conditioned by UC-MSC monolayer (CM2D) and 3D cultures (CM3D). The analysis of relevant trophic factors confirmed secretome profiles with very significant differences in terms of therapeutic potential. Whereas, CM3D was characterised by a prevailing expression of anti-inflammatory cytokines such as IL-10 and LIF, along with trophic factors involved in different mechanisms leading to tissue regeneration, such as PDGF-BB, FGF-2, I-309, SCF, and GM-CSF; CM2D presented relatively higher levels of IL-6, MCP-1, and IL-21, with recognised pro-inflammatory roles in joint disease and pleiotropic effects in the progression of rheumatoid arthritis (RA). Accordingly, different motogenic effects over mouse chondrocytes and distinct capacities of inducing glycosaminoglycan synthesis in vitro were observed between CM3D and CM2D. Finally, the evaluation of arthritic manifestations in vivo, using an adjuvant-induced model for arthritis (AIA), suggested a significantly higher therapeutic potential of CM3D over CM2D and even UC-MSCs. Histological analysis confirmed a faster remission of local and systemic arthritic manifestations of CM3D-treated animals. Overall, the results show that the use of UC-MSC CM3D is a viable and better strategy than direct UC-MSC administration for counteracting AIA-related signs. This strategy represents a novel MSC-based but nonetheless cell-free treatment for arthritic conditions such as those characterising RA.

Cervus and cucumis peptides combined umbilical cord mesenchymal stem cells therapy for rheumatoid arthritis

“…LG polypeptides stimulated UC -MSCs to reduce the release of a pro-inflammatory factor instability of the internal environment, and increase UC-MSCs immune regulation and regenerative biology, which conformed to the principle of the main pathogenesis of TCM. [ 23 , 30 ] This study showed that the improvement of HAQ, DAS28, ESR, CRP, RF, and Anti-CCP in the LG + UC -MSC group was significantly better than that in the UC -MSC group at 1 year after treatment (P < 0.05), and all patients conformed the ACR20 standard. This indicated that TCM intervention played an important role in anti-inflammation, regulating immunity and improving microcirculation in the treatment of UC-MSCs, which was beneficial to the migration of UC-MSCs and repair of damaged tissue.…”

Effect and mechanism of human umbilical cord mesenchymal stem cells in treating allergic rhinitis in mice

“…By regulating the activation of immune cells, they suppress allergic reactions and thus control disease progression. In recent years, mesenchymal stem cells, including hUCMSCs, have been used in animal models or human clinical trials for the treatment of various diseases, such as AR, asthma 31 , osteoarthritis 32 , graft-related diseases such as anti-host disease (GVHD), multiple sclerosis, liver disease 33 , spinal cord injury 34 , diabetes 35 , and systemic lupus erythematosus 36 – 38 . Many studies have found that hUCMSCs play an important role in improving disease treatment by activating Treg cells and inhibiting the production of inflammatory cytokines in AR mouse models 39 , especially at the beginning of the disease.…”

Umbilical Cord MSCs and Their Secretome in the Therapy of Arthritic Diseases: A Research and Industrial Perspective

“…The authors also reported that thrombospondin-2, a glycoprotein mediating cell-to-cell and cell-to-matrix interactions, was the key factor for this process, as it was able to activate in recipient cells different signaling pathways involved in chondrogenesis and cartilage regeneration. ucMSCs were also effective in the treatment of RA, especially when cultured in a 3D environment [61]. In fact, the secretome derived from the 3D culture of these cells, compared to their culture in a 2D environment, resulted richer in anti-inflammatory cytokines (such as IL-10 and LIF) and trophic factors (GM-CSF and many others) and stimulated both mitogenic features and glycosaminoglycan synthesis.…”