Additive Therapeutic Effects of Mesenchymal Stem Cells and IL-37 for Systemic Lupus Erythematosus

Abstract

BackgroundAlthough mesenchymal stem cells (MSCs) might offer a promising strategy for treating SLE, their immunoregulatory plasticity makes their therapeutic effects unpredictable. Whether overexpressing IL-37, an IL-1 family member with immunosuppressive activity, might enhance the therapeutic effects of these cells for SLE is unknown.MethodsWe genetically modified MSCs to overexpress IL-37 and assessed their effects on immune suppression in vitro. We also evaluated the effects of such cells versus effects of various controls after transplanting them into MRL/lpr mice (model of SLE).ResultsStem cell characteristics did not appear altered in MSCs overexpressing IL-37. These cells had enhanced immunosuppression in vitro in terms of inhibiting splenocyte proliferation, reducing proinflammatory factors (IL-1β, TNF-α, IL-17, and IL-6), and suppressing autoantibodies (anti-dsDNA and anti-ANA). Compared with animals receiving control MSCs or IL-37 treatment alone, MRL/lpr mice transplanted with IL-37–overexpressing cells displayed improved survival and reduced signs of SLE (indicated by urine protein levels, spleen weight, and renal pathologic scores); they also had significantly lower expression of proinflammatory factors, lower total antibody levels in serum and urine, lower autoantibody production, and showed reduced T cell numbers in the serum and kidney. Expression of IL-37 by MSCs can maintain higher serum levels of IL-37, and MSCs had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment.ConclusionsMutually reinforcing interaction between MSCs and IL-37 appears to underlie their additive therapeutic effects. Genetic modification to overexpress IL-37 might offer a way to enhance the stability and effectiveness of MSCs in treating SLE.

Cost-effective Storage Solution for Delivering Umbilical Cord with Efficient Isolation of Mesenchymal Stem Cells

“…The fragments were then washed with PBS and replated one more time. The unattached fragments were discarded and the isolated cells were expanded in MSC expansion medium (Dulbecco's Modified Eagle's medium [DMEM]/High Glucose plus 10% fetal bovine serum, 10 ng/ml bFGF) (Peprotech, London, UK), 50 μg/ml vitamin C (Sigma, MO, USA), 100 units/ml penicillin and 100 μg/ml streptomycin [5,21].…”

“…Human MSCs were passaged with TrypLE (ThermoFisher Scientific) for three passages, and then they were subjected to cell surface marker analysis and target differentiation. Differentiation and characterization were performed as described previously [5,21]. Briefly, differentiation was performed with the StemPro R Chondro-genesis Differentiation Kit (Gibco, MA, USA), the StemPro Adipogenesis Differentiation Kit (Gibco) and the StemPro Osteogenesis Differentiation Kit (Gibco) according to manufacturer instructions.…”

Chemical-defined medium supporting the expansion of human mesenchymal stem cells

“…And the human platelet lysate has been used as the standard culture medium for MSCs' clinical applications [13,14]. However, the batch variation of human PL preparation affects the phenotype and function of MSCs [15,16]. Furthermore, the human platelet has limited resources.…”

Improved therapeutic consistency and efficacy of mesenchymal stem cells expanded with chemically defined medium for systemic lupus erythematosus

“…However, batch variation in human PL preparations may affect the phenotype and function of MSCs. Indeed, it has been noted that human PL products from different commercial suppliers show different therapeutic efficacies in treating a mouse model of systemic lupus erythematosus (SLE) 4 . Furthermore, previous investigations have shown that PL upregulates the expression of the costimulatory factors CD40 and CD86 5 , 6 , which may induce immunorecognition and rejection by the host immune system.…”

“…1j ). One of the explanations might be that HLA-ABC, HLA-II and other costimulatory factors might be stimulated by the inflammatory microenvironment in SLE mice 4 . However, the relatively rapid elimination of MSCs during the early stage after transplantation could already reduce MSC therapeutic efficacy.…”