Extracellular vesicles synchronize cellular phenotypes of differentiating cells

During embryonic development, cells differentiate in a coordinated manner, aligning their fate decisions and differentiation stages with those of surrounding cells. However, little is known about the mechanisms that regulate this synchrony. Here we show that cells in close proximity synchronize their differentiation stages and cellular phenotypes with each other via extracellular vesicle (EV)-mediated cellular communication. We previously established a mouse embryonic stem cell (ESC) line harboring an inducible constitutively active protein kinase A (CA-PKA) gene and found that the ESCs rapidly differentiated into mesoderm after PKA activation. In the present study, we performed a co-culture of control ESCs and PKA-ESCs, finding that both ESCs rapidly differentiated in synchrony even when PKA was activated only in PKA-ESCs, a phenomenon we named "Phenotypic Synchrony of Cells (PSyC)". We further demonstrated PSyC was mediated by EVs containing miR-132. PKA-ESC-derived EVs and miR-132-containing artificial nano-vesicles similarly enhanced mesoderm and cardiomyocyte differentiation in ESCs and ex vivo embryos, respectively. PSyC is a new form of cell-cell communication mediated by EV regulation of neighboring cells and could be broadly involved in tissue development and homeostasis.