Intravenous administration of bone marrow-derived mesenchymal stem cells induces a switch from classical to atypical symptoms in experimental autoimmune encephalomyelitis.

Mónica Kurte,Alexander Torres,Carlos E Irarrázabal,Flavio Carrión,Vania Carrasco,Ana María Vega-Letter,Rodrigo A Fuentealba,Cristina Ibáñez,Fernando E Figueroa,Claudia Riedel,Catalina Fernández-O’Ryan,Javiera Bravo-Alegría

doi:10.1155/2015/140170

Abstract

Potent immunosuppressive and regenerative properties of mesenchymal stem cells (MSCs) position them as a novel therapy for autoimmune diseases. This research examines the therapeutic effect of MSCs administration at different disease stages in experimental autoimmune encephalomyelitis (EAE). Classical and atypical scores of EAE, associated with Th1 and Th17 response, respectively, and also Treg lymphocytes, were evaluated. MSCs administration at the onset (EAE+MSConset) induced an important amelioration of the clinical signs and less lasting effect at the peak of EAE (EAE+MSCpeak). No effect was observed when MSCs were applied after EAE stabilization (EAE+MSClate). Surprisingly, EAE atypical signs were detected in EAE+MSCpeak and EAE+MSClate mice. However, no correlation was found in Th17/Th1 ratio. Interestingly, regardless of time administration, MSCs significantly reduced IL-6 and also T-bet, RORγT, and Foxp3 mRNA levels in brain samples of EAE mice. The downregulation of IL-6 could restore the well-functioning of the blood-brain barrier of EAE mice, correlated with a decreased number of brain infiltrating leukocytes. These results suggest that the inflammatory status is important to be considered for administering MSCs in autoimmune pathologies, leading to a further research to clarify the effect of MSCs for multiple sclerosis.

Highlights

Mesenchymal stem cells (MSCs) are adherent, undifferentiated, pluripotent, and nonhematopoietic progenitor cells principally located in bone marrow and adipose tissue, among others [1, 2]
We did not observe an important appearance of atypical signs when MSCs were administered at the onset or to untreated animals (EAE). These results suggest that late MSCs treatments may predispose to the appearance of atypical EAE, and we wanted to analyze central nervous system (CNS) infiltration of different types of T helper lymphocytes that are associated with these clinical signs using a molecular biology approach
Atypical EAE is characterized by ataxia and an immune response biased to Th17 phenotype, in striking contrast to classical EAE, characterized by ascending paralysis and Th1 mediated immune responses

Summary

Introduction

Mesenchymal stem cells (MSCs) are adherent, undifferentiated, pluripotent, and nonhematopoietic progenitor cells principally located in bone marrow and adipose tissue, among others [1, 2]. In vitro expanded MSCs have the potential to differentiate into mesodermal lineages including osteoblasts, chondrocytes, and adipocytes. Mounting evidence demonstrates usefulness for the use of MSCs in tissue repair [3, 4]. MSCs are known for their ability to regulate the immune system. The first reports in 2002-2003 showed that MSCs are able to inhibit. It is well accepted that MSCs have important immunosuppressive properties over the entire immune system, mainly exerting their effects on T, B, NK, and dendritic cells [8, 9]

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