Tunneling nanotubes and EVs in the Developing Heart

Tunneling nanotubes (TNTs) were described very recently. They are thin, long structures that facilitate the transport of cellular components between adjacent cells. The properties of TNTs—including their size and transport capacity—can vary significantly depending on the cell type, differentiation, and health status. Initially, TNTs were described as a means for directly transferring mitochondria between cells, which can rescue diseased cells by supplying healthy mitochondria (1). Additionally, the transfer of mitochondria and lysosomes from stem cells to differentiated cells via mechanisms like tunneling nanotubes suggests this is crucial for tissue repair and regeneration (2). In a recent study, Chen et al. (3) authors developed cardiomyocyte-specific EV reporter mouse lines, with CD9/EGFP as a marker for EVs. They provided evidence of the role of TNT in the developing heart for the transport of extracellular vesicles (EVs). Traditionally, EVs are known to be secreted into the extracellular space and uptake by neighboring cells. Here, the authors highlight that cardiomyocyte-derived EVs primarily transfer through TNTs, necessitating direct cell-to-cell contact. This transfer mode may avoid the clearance of EVs by macrophages, which may occur in the microenvironment. Nevertheless, nanotubes were also observed between cardiomyocytes and macrophages when co-cultured.

The findings revealed that EV uptake by cardiac cells in the developing heart is notably limited without direct cell contact, thus providing new challenges and open questions in paracrine EV transfer under physiological and reparative conditions.