Tumor necrosis factor-α-primed mesenchymal stem cell-derived exosomes promote M2 macrophage polarization via Galectin-1 and modify intrauterine adhesion on a novel murine model

Abstract

BackgroundIntrauterine adhesion (IUA) is a condition caused due to damage or infection of the endometrium. It is characterized by continuous inflammation and following fibrosis and dysfunction. However, the current animal IUA models have several disadvantages, including complex operation, high mortality, and many extra distractions owing to opening of the abdominal cavity to expose the uterus. Mesenchymal stem cells (MSCs), which have been used in treatment of IUA, are heterogeneous and immunosuppressive. However, their therapeutic effect is not as good as expected.MethodsHere, we successfully built a new murine IUA model, called electric tool-scratching IUA model, and applied it in our experiments to investigate the efficacy of tumor necrosis factor-α (TNF-α) primed MSCs (T-MSCs). In the new model, we used a self-made electric tool that can cause mechanical damage to the endometrium without opening the abdominal cavity. ELISA and histological staining analysis were performed to evaluate pathological features of IUA. qRT-PCR, flow cytometry and immunofluoresence staining were performed to detect the phenotypes of macrophages. TMT proteomics quantification and western blotting assay were performed to analyze the differentially expressed proteins of MSC exosomes.ResultsBased on the new IUA model, we found TNF-α pretreatment could enhance the ability of MSCs to relieve inflammation and reduce endometrium fibrosis. Mechanistically, T-MSC promoted macrophage polarization to M2 phenotype through exosomes. Subsequently, we found the expression of Galectin-1 was increased in T-MSC exosomes. Finally, we analyzed the gene expression pattern of Galectin-1 treated macrophages and found Galectin-1 promoted macrophage polarization to M2 phenotype mainly through the Jak-STAT signaling pathway.ConclusionsOur studies proposed an innovative mouse model and a better MSC treatment strategy for IUA.

Validity of stem cell-loaded scaffolds to facilitate endometrial regeneration and restore fertility: a systematic review and meta-analysis

“…Inflammation is critical for triggering local tissue fibrosis and loss of normal functions ( 36 ). Multiple inflammatory factors, such as IL-1β, IL-6, and TNF-α, increase after endometrial damage ( 37 ). Anti-infection and inflammation control are important environmental safeguards to optimize endometrial regeneration.…”

The MSC-EV-microRNAome: A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS

“…Several licensing strategies reliably enhance MSC-derived EV immunoregulatory and therapeutic effects. These priming strategies include pre-exposure to TNFα, IL-1β, IFN-γ alone or in combination [28,75,76,105,[108][109][110][111][112][113][114][115][116][117]; TLR ligands such as LPS [118][119][120], hypoxia [121,122], or other factors, including thrombin [107], the endoplasmic reticulum stress inducer, thapsigargin [123], and the lipophilic photosensitizer, hexyl-5-aminolevulinate hydrochloride (HAL) in combination with pro-inflammatory cytokines [113]; transfection with miR [124]; or serum from injury models [20,34,43], BALF, as above; or secretome from LPS-activated cells such as microglia [125]. EVs derived from licensed or primed MSCs have been investigated in an array of inflammatory conditions and while the pathogenic factors driving specific diseases may differ, there is a large consensus across studies demonstrating the protective and immunoregulatory effects of MSC-derived EVs.…”

Extracellular vesicles mediated gastric cancer immune response: tumor cell death or immune escape?

“…More importantly, miR-200b-3p has also been identified as highly expressed in GC obstructions and possesses oncogenic properties [62]. Additionally, Galectin-1 has been proven to influence macrophages through exosomes, activating the JAK/STAT signaling pathway and inducing M2 polarization [63]. And Galectin-1, highly expressed in GC, promoted tumor progression [64].…”