06 October 2021

Synchronized swimming

Stem cells communicated with membrane vesicles with RNA

Anna Muravyeva, N+1

To synchronize their development, neighboring stem cells exchange membrane vesicles, according to a study published in the Journal of extracellular vesicles (Minakawa et al., Extracellular vesicles synchronize cellular phenotypes of differentiating cells). The vesicles contained miR-132 microRNA, which triggered an accelerated process of cell differentiation. This mechanism of synchronization of embryonic cells during development is discovered for the first time.

Intercellular communication is necessary to maintain the integrity of the body — this is how cells give each other feedback about development, nutrition, environmental stimuli and much more. There are several mechanisms for this: for example, neighboring cells can transmit signaling molecules to each other without any packaging. Also, neighboring cells can form slit contacts and transfer substances through them. And over longer distances, the signal can be transmitted in membrane bubbles, which preserve the substance from destruction.

Intercellular communication between cells of the early embryo is especially important — they will form all organs and tissues of the body from just one zygote. To do this, embryonic stem cells can achieve phenotypic synchronicity — slower cells catch up with their neighbors in the differentiation stage. However, the question of how exactly "fast" cells cause neighbors to accelerate has not yet been studied.

Researchers from Kyoto University, led by Tomohiro Minakawa, have created lines of mouse embryonic stem cells to investigate their communication. To do this, the cells were isolated from early mouse embryos and supported their reproduction in the laboratory. At the same time, biologists forced one of the cell lines to develop and differentiate faster — for this, with the help of genetic engineering, the gene of one of the proteins that trigger differentiation was introduced into the DNA of cells. The degree of cell development was determined by molecular markers corresponding to a particular stage. Then the scientists created cellular aggregates from two types of cells and confirmed synchronization.

Biologists have suggested three possible mechanisms of cell communication for synchronization: regulatory molecules, gaps in the walls of neighboring cells and membrane vesicles — large endosomes or microvesicles. The first decided to test the membrane bubbles — and immediately confirmed the hypothesis. Biologists turned off the enzyme that secretes membrane bubbles out of the cell and checked how cells synchronize at different stages of development. It turned out that without membrane vesicles, the cells really began to communicate worse and remained at different stages (p<0.05).

Then the biologists checked what exactly the cells transmit to each other in the bubbles. All the RNA in the vesicles was sequenced and it was found that 6 types of microRNAs — short regulatory nucleotide sequences - work the most. The researchers created 6 lines, in each of which the synthesis of one of the microRNAs was increased and conducted experiments with cellular aggregates. Only one microRNA, miR—132, significantly increased cell differentiation. To confirm its role in synchronization, biologists turned off its synthesis in one of the cell lines — and the effect really disappeared. After additional analysis, the scientists found that microRNA affects proteins participating in the differentiation pathway and triggers the same cascade of reactions in "slow" cells as in "fast" ones.

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