miR-499 in Platelet-Derived Extracellular Vesicles Augments Inflammatory Cell Generation and Cardiac Remodeling After...

Area of Science:

• Cardiovascular Biology
• Hematology
• Cellular and Molecular Medicine

Background:

• Emergency myelopoiesis by bone marrow hematopoietic stem and progenitor cells (HSPCs) worsens pathology in chronic diseases like myocardial infarction (MI).
• Mechanisms triggering bone marrow myelopoiesis following distant organ injury, such as MI, are not well understood.

Purpose of the Study:

• To investigate the role of platelet-derived extracellular vesicles (pEVs) in mediating emergency myelopoiesis after MI.
• To identify molecular mechanisms by which pEVs influence HSPC behavior and inflammatory cell generation.
• To explore potential therapeutic targets for mitigating cardiac inflammation and remodeling post-MI.

Main Methods:

• Induction of MI in mice via left descending coronary artery ligation.
• Detection and quantification of circulating pEVs in mice and human MI patients using NanoSight, ImageStream, and flow cytometry.
• Assessment of pEVs' effects on HSPC lineage commitment and inflammatory cell generation using parabiosis, flow cytometry, and adoptive transfer experiments.
• RNA sequencing, luciferase assays, and gene overexpression studies to elucidate molecular pathways.

Main Results:

• MI induces a significant increase in circulating pEVs, which promote HSPC proliferation and inflammatory myeloid cell generation in both mice and humans.
• Cardiomyocyte-derived S100A8/9 alarmin complex stimulates pEV secretion; inhibiting platelet activation/exocytosis reduces pEV production and emergency hematopoiesis.
• MI-derived pEVs are enriched with miR-499 and miR-184, which directly promote HSPC proliferation and myelopoiesis by downregulating lactoferrin/lactotransferrin.

Conclusions:

• Platelet-derived extracellular vesicles (pEVs) are key mediators of emergency myelopoiesis and inflammatory cell generation following myocardial infarction (MI).
• The miR-499/lactoferrin axis within pEVs plays a critical role in promoting myelopoiesis and cardiac remodeling post-MI.
• Targeting pEVs and their cargo presents a promising therapeutic strategy to reduce cardiac inflammation and improve outcomes after MI.