Abstract
Extracellular vesicles (EVs) are thought to mediate the transport of proteins and RNAs involved in intercellular communication. Here, we show dynamic changes in the buoyant density and abundance of EVs that are secreted by PC12 cells stimulated with nerve growth factor (NGF), N2A cells treated with retinoic acid to induce neural differentiation, and mouse embryonic stem cells (mESCs) differentiated into neuronal cells. EVs secreted from in vitro differentiated cells promote neural induction of mESCs. Cyclin D1 enriched within the EVs derived from differentiated neuronal cells contributes to this induction. EVs purified from cells overexpressing cyclin D1 are more potent in neural induction of mESC cells. Depletion of cyclin D1 from the EVs reduced the neural induction effect. Our results suggest that EVs regulate neural development through sorting of cyclin D1.
Highlights
Intercellular communication involves either direct contact between neighboring cells or indirect interaction via secreted factors including extracellular vesicles (EVs; Hessvik and Llorente, 2018)
Dynamic changes of EVs secreted by neuronal differentiated PC12 cells We compared EVs secreted from undifferentiated neuronal progenitor-like cells with those secreted by differentiated neuronal cells
nerve growth factor (NGF) is known to stimulate neural gene expression in mouse embryonic stem cells (mESCs), we found that addition of a neutralizing NGF antibody to an incubation of N6-EVs with mESCs did not affect the level of expression of these neural markers, suggesting that possible residual NGF in the EV preparation did not account for this effect (Fig. 4 C)
Summary
Intercellular communication involves either direct contact between neighboring cells or indirect interaction via secreted factors including extracellular vesicles (EVs; Hessvik and Llorente, 2018). Cells release two subtypes of EVs according to their cellular membrane origin: plasma membrane–derived EVs and endosome-derived exosomes (French et al, 2017). Intralumenal vesicles that accumulate within multivesicular bodies (MVBs) are secreted as exosomal EVs to the extracellular environment upon fusion of MVBs with the plasma membrane. Much interest has focused on the wide distribution of EVs in all biological fluids and their potential to trigger intercellular exchange of effector molecules, which may allow secretion of cells to modulate gene expression in target cells and tissues (Mulcahy et al, 2014)
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