Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis

Abstract

Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs’ therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia–reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-β1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.

Serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of mesenchymal stem cells on experimental renal fibrosis

“…This conversion to the active form might require several days. Therefore, prior to administration, preconditioning with various factors, including cytokines [ 17 , 18 ], hypoxia [ 19 , 20 ], pharmacological compounds [ 21 , 22 ], and genetic modification [ 23 , 24 ], has been widely studied to enhance the therapeutic effects of MSCs. We have previously reported that MSCs cultured in STK (Kanto Chemical, Tokyo, Japan), which is serum-free medium containing growth factors for MSC culture, promote their immunosuppressive ability by increasing the expression of tumor necrosis factor-α-induced protein 6 (TSG-6) and inducing polarization of immunosuppressive M2 macrophages, thereby enhancing their anti-fibrotic effect [ 25 ].…”

The Mechanism of CD8+ T Cells for Reducing Myofibroblasts Accumulation during Renal Fibrosis

“…Consistently, Fariba et al suggested the IFN-γ-peptidomimetic fibroferon targeted to PDGFβR-overexpressing myofibroblasts attenuates renal fibrosis [88]. Ryo et al showed that interferon-γ enhances the anti-fibrotic effect of mesenchymal stem cells (MSCs) on experimental renal fibrosis, and it is through the secretion of prostaglandin E2 that MSCs can exert a protective effect on rats subjected to ischemia-reperfusion injury (IRI) and UUO [89]. In recent years, studies from Patrícia et al suggest that, besides NK (through IFN-γ) and dendritic cells (through IL-12), CD8 + T lymphocytes, as another source of IFN-γ, likewise enhances CD4 + Th1 phenotype development [90].…”

Perspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies

“…Additionally, recent studies demonstrated that MSC culture in vitro and preparation prior to transplantation might affect the therapeutic properties. Indeed, two independent studies showed that the use of BM-MSCs pretreated with melatonin or IFNγ ameliorated interstitial fibrosis compared with control groups [198,199]. Similarly, amniotic fluid-derived stem cells (AFSCs), which exhibit characteristics of both ESCs and MSCs, preconditioned with GDNF, were shown to abrogate the degree of renal interstitial fibrosis in mice [200].…”