M1 macrophage-derived exosomes inhibit cardiomyocyte proliferation through delivering miR-155

• Published in: BMC cardiovascular disorders Vol. 24; no. 1; pp. 365 - 11
• Main Authors: He, Xiaoqing, Liu, Shan, Zhang, Zhanyu, Liu, Qirui, Dong, Juan, Lin, Zhifeng, Chen, Junhao, Li, Lihuan, Liu, Weihua, Liu, Shaojun, Liu, Shiming
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16.07.2024; BioMed Central; BMC
• Subjects: Analysis; Animals; Antibodies; Cardiomyocyte proliferation; Cardiomyocytes; Care and treatment; Cell Proliferation - drug effects; Cells, Cultured; Coculture Techniques; Diagnosis; Disease Models, Animal; Exosomes; Exosomes - genetics; Exosomes - metabolism; Exosomes - transplantation; Granulocyte-macrophage colony-stimulating factor; Heart; Heart attack; Heart cells; Heart failure; Immunoblotting; Immunofluorescence; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - metabolism; Interleukins; Janus kinase; Janus kinase 2; Janus Kinase 2 - metabolism; Laboratory animals; M1 macrophage; Macrophages; Macrophages - metabolism; Male; Mice, Inbred C57BL; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Mir-155; miRNA; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Penicillin; Phosphorylation; Rats, Sprague-Dawley; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Regeneration; Reporter gene; Risk factors; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; γ-Interferon; China; Cardiomyocyte proliferation; Myocardial infarction; Mir-155; Exosomes; M1 macrophage
• ISSN: 1471-2261; 1471-2261
• DOI: 10.1186/s12872-024-03893-0

M1 macrophages are closely associated with cardiac injury after myocardial infarction (MI). Increasing evidence shows that exosomes play a key role in pathophysiological regulation after MI, but the role of M1 macrophage-derived exosomes (M1-Exos) in myocardial regeneration remains unclear. In this study, we explored the impact of M1 macrophage-derived exosomes on cardiomyocytes regeneration in vitro and in vivo. M0 macrophages were induced to differentiate into M1 macrophages with GM-CSF (50 ng/mL) and IFN-γ (20 ng/mL). Then M1-Exos were isolated and co-incubated with cardiomyocytes. Cardiomyocyte proliferation was detected by pH3 or ki67 staining. Quantitative real-time PCR (qPCR) was used to test the level of miR-155 in macrophages, macrophage-derived exosomes and exosome-treated cardiomyocytes. MI model was constructed and LV-miR-155 was injected around the infarct area, the proliferation of cardiomyocytes was counted by pH3 or ki67 staining. The downstream gene and pathway of miR-155 were predicted and verified by dual-luciferase reporter gene assay, qPCR and immunoblotting analysis. IL-6 (50 ng/mL) was added to cardiomyocytes transfected with miR-155 mimics, and the proliferation of cardiomyocytes was calculated by immunofluorescence. The protein expressions of IL-6R, p-JAK2 and p-STAT3 were detected by Western blot. The results showed that M1-Exos suppressed cardiomyocytes proliferation. Meanwhile, miR-155 was highly expressed in M1-Exos and transferred to cardiomyocytes. miR-155 inhibited the proliferation of cardiomyocytes and antagonized the pro-proliferation effect of interleukin 6 (IL-6). Furthermore, miR-155 targeted gene IL-6 receptor (IL-6R) and inhibited the Janus kinase 2(JAK)/Signal transducer and activator of transcription (STAT3) signaling pathway. M1-Exos inhibited cardiomyocyte proliferation by delivering miR-155 and inhibiting the IL-6R/JAK/STAT3 signaling pathway. This study provided new insight and potential treatment strategy for the regulation of myocardial regeneration and cardiac repair by macrophages.