SnRNA sequencing defines signaling by RBC-derived extracellular vesicles in the murine heart

Area of Science:

• Cardiovascular Biology
• Cellular Signaling
• Extracellular Vesicles

Background:

• Extracellular vesicles (EVs) mediate intercellular communication, but their functional roles, especially in heart disease, are not fully understood.
• Red blood cell (RBC)-derived EVs are abundant in circulation and play a role in immune responses.
• Understanding EV-mediated signaling in the context of heart conditions is crucial.

Purpose of the Study:

• To investigate the role of RBC-derived EVs in intercellular signaling within the context of ischemic heart failure.
• To identify recipient cells targeted by RBC-EVs in the heart using a novel mapping technique.
• To elucidate the functional consequences of RBC-EV targeting in cardiomyocytes.

Main Methods:

• Development of a transgenic mouse model for fluorescence-based mapping of RBC-EV recipient cells.
• Induction of ischemic heart failure in the mouse model.
• Single cell nuclear RNA sequencing (scNucRNA-seq) to analyze gene expression in targeted cardiac cells.
• Assessment of cellular markers for DNA synthesis in RBC-EV-targeted cardiomyocytes.

Main Results:

• An increased number of RBC-EV-targeted cardiomyocytes were detected in a murine model of ischemic heart failure.
• scNucRNA-seq revealed a complex cellular network of RBC-EV recipients in the heart.
• Targeted cardiomyocytes showed enrichment in genes related to cell proliferation and stress signaling pathways.
• RBC-EV-targeted cardiomyocytes exhibited increased expression of DNA synthesis markers.

Conclusions:

• The study establishes a mouse model for mapping EV recipient cells, revealing intricate RBC-EV-mediated intercellular communication in ischemic heart failure.
• RBC-EVs play a functional role in intercellular signaling within the failing heart.
• EV-mediated signaling contributes to cellular responses, including proliferation and stress, in cardiomyocytes during heart disease.