Enhanced Therapeutic Effects of Apoptotic Cell Conditioned Mesenchymal Stem Cells in Lupus-Prone MRL/lpr Mice

Abstract

Background: Our previous study showed that apoptotic cell conditioned mesenchymal stem cells (AC-MSCs) obtained stronger T cell suppressive ability via cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2), but whether AC-MSCs exhibit enhanced therapeutic effect on systemic erythematosus lupus (SLE) remains unknown. In this study, we aim to explore the efficacy and possible mechanism of AC-MSCs in ameliorating SLE. Methods: Splenocytes from MRL/MPJ-Faslpr (MRL/lpr) mice were co-cultured with AC-MSCs and the proportions of plasma cells (PCs) were detected by flow cytometry. MSCs and AC-MSCs, COX2 knock-down MSCs and COX2 knock-down AC-MSCs were infused into MRL/lpr mice respectively. Survival rates and lupus symptoms including proteinuria, kidney injury, renal immune complex deposition and autoantibody production were assessed. Besides, the numbers of PCs and serum inflammatory cytokines were measured. Results: We found that AC-MSCs possessed stronger ability on PC inhibition via PGE2 in vitro. AC-MSC treatment led to significantly higher survival rate. Moreover, AC-MSC infusion decreased proteinuria levels as early as one week after infusion. Both of MSC and AC-MSC administration reduced renal immunoglobulin (Ig)G and complement C3 deposition, whereas COX2 knock-down MSCs and COX2 knock-down AC-MSCs could not. Serum anti-dsDNA antibody levels in AC-MSCs treated mice significantly decreased, as well as the number of PCs in both spleen and renal draining lymph node. In addition, AC-MSCs inhibit the production of inflammatory cytokines including interleukin (IL)-21, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. Conclusions: AC-MSCs exhibited enhanced therapeutic effects on lupus mice, which was partially mediated by COX2/PGE2. Our findings indicate that AC precondition may be a new strategy for MSC transplantation in treating SLE.