Galectin-3 Knockdown Impairs Survival, Migration, and Immunomodulatory Actions of Mesenchymal Stromal Cells in a Mouse Model of Chagas Disease Cardiomyopathy.

Bruno Solano de Freitas Souza,Milena Botelho Pereira Soares,Carolina Kymie Nonaka,Bruno Diaz Paredes,Carine Machado Azevedo,Daniela Nascimento Silva,Juliana Fraga Vasconcelos,Vinícius Pinto Costa Rocha,Ricardo Ribeiro dos Santos,Gisele Batista Carvalho,Kátia Nunes da Silva

doi:10.1155/2017/3282656

Bruno Solano de Freitas Souza, Milena Botelho Pereira Soares

Open Access

https://doi.org/10.1155/2017/3282656

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Journal: Stem cells international	Publication Date: Jan 1, 2017
Citations: 23	License type: CC BY 4.0

Abstract

Therapies based on transplantation of mesenchymal stromal cells (MSC) hold promise for the management of inflammatory disorders. In chronic Chagas disease cardiomyopathy (CCC), caused by chronic infection with Trypanosoma cruzi, the exacerbated immune response plays a critical pathophysiological role and can be modulated by MSC. Here, we investigated the role of galectin-3 (Gal-3), a beta-galactoside-binding lectin with several actions on immune responses and repair process, on the immunomodulatory potential of MSC. Gal-3 knockdown in MSC did not affect the immunophenotype or differentiation potential. However, Gal-3 knockdown MSC showed decreased proliferation, survival, and migration. Additionally, when injected intraperitoneally into mice with CCC, Gal-3 knockdown MSC showed impaired migration in vivo. Transplantation of control MSC into mice with CCC caused a suppression of cardiac inflammation and fibrosis, reducing expression levels of CD45, TNFα, IL-1β, IL-6, IFNγ, and type I collagen. In contrast, Gal-3 knockdown MSC were unable to suppress the immune response or collagen synthesis in the hearts of mice with CCC. Finally, infection with T. cruzi demonstrated parasite survival in wild-type but not in Gal-3 knockdown MSC. These findings demonstrate that Gal-3 plays a critical role in MSC survival, proliferation, migration, and therapeutic potential in CCC.

Highlights

Mesenchymal stromal cells (MSC) are multipotent stem cells with the ability to differentiate into mesoderm-derived cell lineages, such as chondrocytes, osteocytes, and adipocytes [1]
Bone marrow-derived MSC lines were generated by transduction with lentiviral vectors containing the shRNA sequence targeting Gal-3 gene or a nontargeting scrambled sequence
We found that Gal-3 knockdown MSC present decreased proliferation rate when compared to controls, as measured by 3H-thymidine incorporation (Figure 3(a))

Summary

Introduction

Mesenchymal stromal cells (MSC) are multipotent stem cells with the ability to differentiate into mesoderm-derived cell lineages, such as chondrocytes, osteocytes, and adipocytes [1]. MSC can be obtained from different organs and tissues of adult individuals, being presently among the most studied cell types in cell therapies [1]. The potential use of MSC to treat inflammatory and autoimmune disorders is based on several described immunomodulatory actions, including inhibition of the activation of T and B lymphocytes, NK cells, and dendritic cells and stimulation of regulatory T cell differentiation [3]. The antiinflammatory actions of MSC are well studied and found to be mediated by IL-10, TGF-β, PGE2, HGF, and IDO (for human cells) or iNOS (for mouse cells). Galectin-3 (Gal-3) has been suggested as a critical mediator of immunomodulatory actions of human MSC [4, 5]

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Conclusion