Enhanced therapeutic effects of apoptotic cell‐conditioned mesenchymal stem cells in lupus‐prone MRL/lpr mice

Abstract

Abstract Background Apoptotic cell‐conditioned mesenchymal stem cells (AC‐MSCs) exhibit stronger T cell suppressive ability via cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2); however, whether AC‐MSCs exhibit enhanced therapeutic effects on systemic lupus erythematosus (SLE) remains unknown. Methods Splenocytes from MRL/MPJ‐Faslpr (MRL/lpr) mice were cocultured with AC‐MSCs, and the proportion of plasma cells was determined by flow cytometry. MSCs, AC‐MSCs, COX2 knockdown MSCs, and COX2 knockdown AC‐MSCs were infused into MRL/lpr mice (n = 10/group). Survival rates and lupus symptoms, including proteinuria, kidney injury, renal immune complex deposition, and autoantibody production, were assessed. Additionally, the number of plasma cells and serum levels of inflammatory cytokines were measured. Results The AC‐MSCs significantly inhibited plasma cells via PGE2 after 24 h coculture in vitro, whereas MSCs did not. In the MRL/lpr mice, AC‐MSC treatment led to a significantly higher survival rate than phosphate‐buffered saline (PBS) treatment (90% vs. 50%, p < 0.05). Moreover, AC‐MSC infusion decreased urine protein levels as early as 1 week after administration (0.89 ± 0.55 mg/mL vs. 1.59 ± 0.60 mg/mL, p < 0.05, compared with PBS treatment). Administration of both MSCs and AC‐MSCs reduced renal immunoglobulin G and complement C3 deposition, whereas COX2 knockdown MSCs and COX2 knockdown AC‐MSCs did not. Serum anti‐dsDNA antibody levels in AC‐MSC‐treated mice significantly decreased (0.40 ± 0.25 vs. 0.99 ± 0.58, p < 0.05), compared with PBS treatment, as well as the number of plasma cells in both the spleen ([2.14 ± 1.05] × 106 vs. [8.02 ± 4.01] × 106, p < 0.01) and renal‐draining lymph nodes ([0.78 ± 0.68] × 106 vs. [2.49 ± 1.45] × 106, p < 0.05). Additionally, AC‐MSCs inhibited the production of inflammatory cytokines, including interleukin‐21, tumor necrosis factor‐alpha, and monocyte chemoattractant protein‐1. Conclusions AC‐MSCs enhanced the therapeutic effects in mice with lupus, which were partially mediated by COX2/PGE2. Therefore, AC preconditioning may be a new strategy for MSC transplantation in the treatment of SLE.

Keywords

• apoptotic cells
• mesenchymal stem cells
• precondition
• prostaglandin E2
• systemic lupus erythematosus