The therapeutic potential of mesenchymal stem cells (MSCs) has been investigated in many preclinical and clinical studies. This potential is dominantly based on the immunosuppressive properties of MSCs. Although the therapeutic profiles of MSC transplantation are still not fully characterized, accumulating evidence has revealed that B cells change after MSC infusion, in particular inducing regulatory B cells (Bregs). The immunosuppressive effects of Bregs have been demonstrated, and these cells are being evaluated as new targets for the treatment of inflammatory diseases. MSCs are capable of educating B cells and inducing regulatory B cell production via cell-to-cell contact, soluble factors, and extracellular vesicles (EVs). These cells thus have the potential to complement each other's immunomodulatory functions, and a combined approach may enable synergistic effects for the treatment of immunological diseases. However, compared with investigations regarding other immune cells, investigations into how MSCs specifically regulate Bregs have been superficial and insufficient. In this review, we discuss the current findings related to the immunomodulatory effects of MSCs on regulatory B cells and provide optimal strategies for applications in immune-related disease treatments.

Background: To clarify the effect of human umbilical cord-derived mesenchymal stem cell (hUC-MSCs) treatment on colitis and to explore the role of CD5⁺ B cells in MSC therapy. Methods: The trinitrobenzenesulfonic acid (TNBS)-induced colitis mouse model was used. HUC-MSCs were transferred peritoneally. Survival rates, colitis symptoms, and macroscopic and histologic scores were evaluated. CD4⁺ T helper (Th) cell subgroups and CD5⁺ regulatory B cell (Bregs) in lymphocytes were quantitated by flow cytometry. Cytokine levels were detected by ELISA and Bio-plex. CD5⁺ B cells were isolated for in vitro co-culture and adaptive transfer. Results: HUC-MSC treatment alleviated TNBS-induced colitis by increasing survival rates, relieving symptoms, and improving macroscopic and histologic scores. Labeled hUC-MSCs were located in the inflamed areas of colitis mice. Increases in regulatory T cells (Tregs) and CD5⁺ B cells and decreases in Th1 cells, Th17 cells, and several pro-inflammatory cytokines were observed with hUC-MSC treatment. After adaptive transfer, CD5⁺ B cells, which were located mainly in the peritoneal lavage fluid, improved TNBS-induced colitis by correcting Treg/Th1/Th17 imbalances. CD5⁺ B cells also inhibited T-cell proliferation and produced interleukin (IL)-10. Conclusions: HUC-MSCs protected against experimental colitis by boosting the numbers of CD5⁺ B cells and IL-10-producing CD5⁺ Bregs, and correcting Treg/Th17/Th1 imbalances.

Mesenchymal stromal cells (MSCs) have become a promising treatment for inflammation-related diseases, and their therapeutic efficacy mainly depends on crosstalk between MSCs and inflammation. However, methods to improve the immunosuppressive efficiency of MSCs in different diseases still need to be developed. In this study, we investigated whether preconditioning MSCs with a disease-related inflammatory cytokine could increase their immunosuppressive properties and improve therapeutic efficacy. In a contact hypersensitivity (CHS) mouse model, inflammatory profile screening revealed that among all tested cytokines, monocyte chemotactic protein-1 (MCP-1) exhibited the most significantly increased level in the local microenvironment. As expected, MSCs preconditioned with MCP-1 (P-MSCs) exhibited an enhanced ability to downregulate proinflammatory cytokine secretion, induce regulatory T cells, inhibit T cell proliferation, and polarize M2-type macrophages. In vivo experiments showed that P-MSCs alleviated ear swelling and local proinflammatory cytokine production more effectively than control MSCs. Mechanistically, MCP-1 could significantly activate the signal transducer and activator of transcription 3 (STAT3) signaling pathway and induce the expression of cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) in MSCs. STAT3 inhibitor reversed the MCP-1-mediated enhancing of their immunosuppressive ability. Collectively, our findings demonstrate that CHS-related MCP-1 preconditioning enhanced the immunomodulatory effects of MSCs and improved their therapeutic efficacy in CHS. Enhancing the immunosuppressive efficacy of MSCs by preconditioning with certain disease-related inflammatory cytokines may provide a new strategy for MSC-based therapies for inflammatory diseases.

Heart transplantation is the final life-saving therapeutic strategy for many end-stage heart diseases. Long-term immunosuppressive regimens are needed to prevent allograft rejection. Mesenchymal stromal cells (MSCs) have been shown as immunomodulatory therapy for organ transplantation. However, the effect of dose and timing of MSC treatment on heart transplantation has not yet been examined. In this study, we infused three doses (1 × 10 ⁶ , 2 × 10 ⁶ , or 5 × 10 ⁶ cells) of human MSCs (hMSCs) to the recipient BALB/c mice before (7 days or 24 h) or after (24 h) receiving C57BL/6 cardiac transplants. We found that infusion of high dose hMSCs (5 × 10 ⁶ ) at 24 h post-transplantation significantly prolonged the survival time of cardiac grafts. To delineate the underlying mechanism, grafts, spleens, and draining lymph nodes were harvested for analysis. Dose-dependent effect of hMSC treatment was shown in: (1) alleviation of International Society of Heart and Lung Transplantation (ISHLT) score in grafts; (2) reduction of the population of CD4 ⁺ and CD8 ⁺ T cells; (3) increase of regulatory T (Treg) cells; (4) and decrease of serum levels of inflammatory cytokines and donor-specific antibodies. Taken together, we showed timing critical and dose-dependent immunomodulatory effects of hMSC treatment against acute allograft rejection in a mouse model of heart transplantation.