Galectin-3 Derived from HucMSC Exosomes Promoted Myocardial Fibroblast-to-Myofibroblast Differentiation Associated with β-catenin Upregulation

Abstract

Background and Objectives: Galectin-3 promotes fibroblast-to-myofibroblast differentiation and facilitates injury repair. Previous studies have shown that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) promote the differentiation of myocardial fibroblasts into myofibroblasts under inflammatory environment. Whether hucMSC-ex derived Galectin-3 (hucMSC-ex-Galectin-3) plays an important role in fibroblast-to-myofibroblast differentiation is the focus of this study. Methods and Results: Galectin-3 was knocked-down by siRNA in hucMSCs, and then exosomes were extracted. Fibroblasts were treated with LPS, LPS＋hucMSC-ex, LPS＋negative control-siRNA-ex (NC-ex), or LPS＋ Galectin-3-siRNA-ex (si-ex) in vitro. The coronary artery of the left anterior descending (LAD) branch was permanently ligated, followed by intramyocardial injection with phosphate buffered saline(PBS), hucMSC-ex, hucMSC-NC-ex, or hucMSC-si-ex in vivo. Western blot, RT-PCR, and immunohistochemistry were used to detect the expression of markers related to fibroblast-to-myofibroblast differentiation and inflammatory factors. Migration and contraction functions of fibroblasts were evaluated using Transwell migration and collagen contraction assays, respectively. β-catenin expression was detected by western blot and immunofluorescence. The results showed that hucMSC-ex increased the protein expression of myofibroblast markers, anti-inflammatory factors, and β-catenin. HucMSC-ex also reduced the migration and promoted the contractility of fibroblasts. However, hucMSC-si-ex did not show these activities. Conclusions: HucMSC-ex-Galectin-3 promoted the differentiation of cardiac fibroblasts into myofibroblasts in an inflammatory environment, which was associated with increased β-catenin levels.

Shikonin reduces M2 macrophage population in ovarian cancer by repressing exosome production and the exosomal galectin 3-mediated β-catenin activation

“…In addition, GAL3 has been reported to increase nuclear translocation and activation of β-catenin by promoting glycogen synthase kinase-3beta phosphorylation and reducing its activity [ 21 ], and GAL3-mediated β-catenin has been correlated with metastasis of hepatocellular carcinoma [ 46 ]. The exosomal GAL3 level has also been correlated with β-catenin level [ 47 ]. The aberrant activation of β-catenin signaling is closely correlated with various human diseases, including cancer, and it participates in a wide array of tumorigenic events from onset to development [ 48 ].…”

The potential roles of galectin-3 in AKI and CKD

“…Evidence from multiple studies demonstrates that myeloid cellderived Gal3 drives acute and chronic inflammation, including infection-mediated inflammation, and warrants further evaluation of Gal3 as a therapeutic target (Ferreira et al, 2018;Wang et al, 2019;Chiu et al, 2020;Guo et al, 2021;Humphries et al, 2021). In a clinical cohort study, median Gal3 concentrations were elevated 1.4-fold in pneumonia and 2.7-fold in sepsis (Mueller et al, 2015).…”

Mechanisms and Optimization Strategies of Paracrine Exosomes from Mesenchymal Stem Cells in Ischemic Heart Disease

“…When the dead cells are removed, cardiac repair enters the proliferative stage. During this stage, the inflammatory response is suppressed, and most fibroblasts differentiate into myofibroblasts, exhibiting an anti-inflammatory phenotype and producing an ECM that enhances the contractile capacity of the myocardium to maintain the structural and functional integrity of the heart [ 91 ]. Therefore, it may be beneficial for the increase of myocardial fibroblasts during the inflammatory period after MI to cardiac repair after MI [ 89 ].…”

“…Moreover, galectin-3 is a key protein associated with modulation of the Wnt/ β -catenin signaling pathway. Guo et al [ 91 ] observed in a rat MI model that galectin-3 in hUCMSC-Exos promoted the differentiation of CFs into myofibroblasts in an inflammatory environment by upregulating β -catenin levels in fibroblasts. Notably, an appropriate increase in the Wnt signaling pathway can promote the repair of necrotic myocardial tissue after MI, reduce the size of MI, and improve ventricular function [ 95 , 96 ].…”