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

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.

Role of MSC-derived galectin 3 in the AML microenvironment

“…Suppression of LGALS3 in MSC reduces MSC abilit y to inhibit T cell function (24, 44). Recent studies have suggested LGALS3 plays an important role in MSC migration (38, 47). A study of LGALS3 in murine MSC revealed that the galectin is elevated in MSC as mice age (48).…”

The Emerging Role of Galectins and O-GlcNAc Homeostasis in Processes of Cellular Differentiation

“…The expression of galectin-3 was gradually increased in maturing myeloid cells isolated from human bone marrow and more galectin-3 was detected on the cell surface, which might represent secreted galectin-3 [ 55 ]. The myeloid progenitor cells from the bone of galectin-3-knockout mice showed a limited capacity to differentiate into mature myeloid and monocyte cell populations [ 145 ], while mesenchymal stromal cells with galectin-3 knockdown were able to differentiate into adipocytes, osteocytes, and chondrocytes [ 146 ]. In comparison, galectin-3-deficient mouse hepatic progenitor cells were more prone than primary cells to differentiate into biliary cells and mature hepatocytes demonstrating a lineage-dependent role of galectin-3 [ 147 ].…”

Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

“…Galectin-3 is important for the adhesion and chemotaxis of monocyte/macrophage cells and the migration of these cells through the endothelium [ 101 ], and due to its function as receptor for PAMPs enhances the phagocytic and microbicidal activity of phagocytes. Specifically, this molecule recognizes and binds to glycoconjugates, on the surface of pathogens such as: Neisseria gonorrhoeae, Leishmania major, Schistosoma mansoni and Trypanosoma cruzi , and also stimulates opsonization [ 141 , 142 , 143 , 144 , 145 ].…”