Improved Protective Effect of Umbilical Cord Stem Cell Transplantation on Cisplatin-Induced Kidney Injury in Mice Pretreated with Antithymocyte Globulin.

Željka Večerić-Haler,Snežna Sodin Šemrl,Andreja Erman,Katja Lakota,Martina Perše,Miha Arnol,Helena Motaln,Anton Cerar,Tamara Lah Turnšek,Katja Kološa,Špela Škrajnar,Katjuša Mrak-Poljšak,Simona Kranjc

doi:10.1155/2016/3585362

Abstract

Mesenchymal stem cells (MSCs) are recognised as a promising tool to improve renal recovery in experimental models of cisplatin-induced acute kidney injury. However, these preclinical studies were performed on severely immunodeficient animals. Here, we investigated whether human umbilical cord derived MSC treatment could equally ameliorate acute kidney injury induced by cisplatin and prolong survival in mice with a normal immune system and those with a suppressed immune system by polyclonal antithymocyte globulin (ATG). We demonstrated that ATG pretreatment, when followed by MSC transplantation, significantly improved injured renal function parameters, as evidenced by decreased blood urea nitrogen and serum creatinine concentration, as well as improved renal morphology. This tissue restoration was also supported by increased survival of mice. The beneficial effects of ATG were associated with reduced level of inflammatory protein serum amyloid A3 and induced antioxidative expression of superoxide dismutase-1 (SOD-1), glutathione peroxidase (GPx), and hem oxygenase-1 (HO-1). Infused MSCs became localised predominantly in peritubular areas and acted to reduce renal cell death. In conclusion, these results show that ATG diminished in situ inflammation and oxidative stress associated with cisplatin-induced acute kidney injury, the effects that may provide more favourable microenvironment for MSC action, with consequential synergistic improvements in renal injury and animal survival as compared to MSC treatment alone.

Highlights

Over the last decade, mesenchymal stem cells (MSCs) were shown to be one of the promising tools to treat acute kidney injury (AKI) in various animal models, including cisplatin-induced nephrotoxicity [1,2,3]
We investigated whether human umbilical cord derived Mesenchymal stem cells (MSCs) treatment could ameliorate acute kidney injury induced by cisplatin and prolong survival in mice with a normal immune system and those with a suppressed immune system by polyclonal antithymocyte globulin (ATG)
We demonstrated that ATG pretreatment, when followed by MSC transplantation, significantly improved injured renal function parameters, as evidenced by decreased blood urea nitrogen and serum creatinine concentration, as well as improved renal morphology

Summary

Introduction

Mesenchymal stem cells (MSCs) were shown to be one of the promising tools to treat acute kidney injury (AKI) in various animal models, including cisplatin-induced nephrotoxicity [1,2,3]. It has been shown that MSC transplantation markedly improved animal survival as well as functional and morphological parameters of cisplatin-induced AKI [4,5,6,7,8]. MSCs from human umbilical cord have been successfully used in cell therapies as immunoregulators for the treatment of GVHD in humans [12] and in various immunocompetent animal models without the use of immunosuppressants for the treatment of targeted diseases [13], including cisplatin nephrotoxicity [2]. Most of the studies that evaluated beneficial effects of human MSCs in cisplatin-induced AKI have been so far performed on immunocompromised animals [4, 6]

Objectives

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Results