Double-Edged Effect of Hydroxychloroquine on Human Umbilical Cord-Derived Mesenchymal Stem Cells Treating Lupus Nephritis in MRL/lpr Mice

Abstract

Hydroxychloroquine (HCQ) and human umbilical cord-derived mesenchymal stem cells (UC-MSCs) were used to treat systemic lupus erythematosus (SLE), respectively. However, the effect of HCQ on UC-MSCs in lupus nephritis (LN) has not been investigated. In this study, HCQ and UC-MSCs were used in MRL/lpr mice. Surprisingly, although the treatment of both HCQ and UC-MSCs could ameliorate renal damage separately, the presence of HCQ decreased unexpectedly the therapeutic effects of UC-MSCs through interfering expression of IFN-γ. However, HCQ-pretreated UC-MSCs showed significant improvements of renal morphology and function more rapidly than that of UC-MSCs and HCQ alone. To test the role of HCQ in UC-MSCs, MRL/lpr mice and SLE patients' peripheral blood were used in vivo and in vitro. Results showed that after administration of UC-MSCs pretreated by HCQ, CXCR3 expression in renal tissues, serum IL-2, and IgM levels decreased significantly, and serum IL-10 level increased significantly. HCQ pretreatment caused a significant decrease of TNF-α and MCP-1 secretion and an increase of IL-1β and CXCL10 release from UC-MSCs. Our results indicate that HCQ plays a double-edged role in UC-MSCs. It is necessary for clinical treatment to pre-evaluated concomitant application of UC-MSCs with HCQ. More importantly, the alterative expression of IFN-γ, the improvement of migration ability of UC-MSCs, the regulation of Th1/Th2 balance, and the changes of antibodies secretion in B cell might be involved in its mechanisms.

Efficacy of mesenchymal stem cells in animal models of lupus nephritis: a meta-analysis

“…Three experimental studies [10,19,30] were identified in this meta-analysis to detect the effect of MSC Table 2). Table 2).…”

“…The levels of TGF-β, MCP-1, IFN-γ, TNF-α, Th1, Th17, Foxp3, and Tregs were detected; three studies [10,18,24] for TGF-β, two studies [11,37] for MCP-1, four studies [12,20,24,30] for IFN-γ, six studies [12,16,20,24,35,37] for TNF-α, three studies [19,23,37] for Th1, four studies [19,23,26,36] for Th17, two studies [10,11] for Foxp3, and three studies [19,23,36] for Tregs were included for the assessment of the effect of MSC treatment on other cytokines. Interestingly, the MSC treatment group had a lower level of IFN-γ when compared with the control group (OR = − 240.24, 95% CI − 364.73, − 115.75; P = 0.0002; Table 2).…”

What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment?

“…In addition, serum levels of albumin, antibodies, and the complement, as well as the number of peripheral blood leukocytes, platelets, and 24-h proteinuria level, were all improved [35,36]. HUC-MSCs can play a role in the treatment of SLE by inhibiting the proliferation of T cells, increasing the number of Treg cells, inhibiting the expansion of Tfh cells, maintaining the balance between T helper 1 and T helper 2 cells (Th1/Th2), and decreasing the level of TNF-α and IL-17 [37,38]. In addition, certain microRNAs (miR-NAs) are implicated in immune diseases, and the treatment of SLE by HUC-MSCs upregulated the expression of miR-153-3p and miR-181a [39,40].…”

The therapeutic applications of mesenchymal stromal cells from human perinatal tissues in autoimmune diseases

“…In addition to UCMSCs, PDMSCs can also reduce the severity of proteinuria and the production of anti-dsDNA antibodies in addition to ameliorating renal pathological changes by inhibiting the expression of inflammatory cytokines, including nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), and so on [58]. Furthermore, besides untreated MSCs used for LN, hydroxychloroquine-pretreated UCMSCs have also been researched to obtain better therapeutic effect than that of untreated UCMSCs, suggesting appropriate pretreatment of MSCs before transplantation can promote better clinical outcomes [59].…”