Extracellular vesicles coordinate intercellular signaling within the hearts pacemaker.

National Institute On Aging

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Abstract

Using immunocytochemical, transmission electron microscopy and live tissue imaging techniques we detected a wide-ranging release of extracellular vesicles in SAN tissue, frequently from S100B positive interstitial cells towards the primary HCN4 positive pacemaker cells and identified selective uptake of EVs by pacemaker cells. These EVs contain important cargo involved in regulation of SAN composition and function. Specifically, we identified in SAN EVs Ca2+-binding protein S100B that we have shown to act as an important regulatory protein influencing heart rhythm regulation. Additionally, we have identified in SAN EVs transcriptional factor TBX3 and signaling molecules BMP2/BMP4 that have been previously implicated in maintaining high levels of HCN4 expression while blocking the expression of CX43, the hallmarks of the primary pacemaker cells. Application of S100B to SAN preparations desynchronized Ca 2+ signaling in HCN4 expressing cells, and increased variability in SAN impulse rate and rhythm. Conclusions: We discovered that the EF-hand Ca2+ binding protein, S100B is the cargo of SAN EVs and that release of EVs with S100b has an important regulatory function on SAN rhythmic impulse formation. S100B was found to desynchronize Ca 2+ signaling in HCN4 expressing cells, and to increase variability in SAN impulse rate and rhythm. We conclude that EVs within SAN tissue mediate intercellular communication by carrying and transporting functional signaling molecules as cargo from the interstitial cell towards pacemaker cells and thus play important role not only in the modulation of heart rhythm but also in maintaining the pacemaker cell phenotype.