How Stem Cells Choose their Fate

The fate of stem cells was linked to microRNA

Oleg Lischuk, N+1 based on EMBL: Forever young: how stem cells resist change

German scientists have found out the molecular mechanism of self-renewal of stem cells, which allows them to either maintain pluripotency (the ability to develop into different cells), or differentiate into cells of a certain tissue. The results of the study are published in Molecular Systems Biology (Sladitschek, Neveu: The bimodally expressed microRNA miR‐142 gates exit from pluripotency.

For their work, the staff of the European Laboratory of Molecular Biology in Heidelberg have developed a reporter system that allows you to track the activity of microRNAs in individual cells. It is a bidirectional promoter that controls the expression of a fluorescent dye-a red normalizer (histone H2B-mCherry) and a green microRNA detector (H2B-Citrine). The shade resulting from their mixing makes it possible to quantify the expression of a given type of microRNA in a cell.

Using this system, the researchers studied the activity of 33 of the most evolutionarily preserved microRNAs associated with differentiation, pluripotency and proliferation in mouse embryonic stem cells. It turned out that the expression level of microRNA-142 (miR-142) it can be high and low, which is why cells that are indistinguishable by pluripotency markers can be in two different states.

Using modeling and quantitative experimental data, the scientists came to the conclusion that embryonic stem cells can switch between these states randomly. At the same time, cells with a high content of miR-142 self–renew, maintaining pluripotency and not reacting to external influences, and with a low one - respond to the presence of differentiation factors.

Under suitable conditions, cells with low levels of miR-142 (green on the left) differentiated into neurons (pink on the right). Cells with high levels of miR-142 (red on the left, blue on the right) retained pluripotency.
EMBL / Hanna Sladitschek

Further investigation showed that the regulation by miR-142 of the ability of cells to differentiate occurs according to the principle of double negative feedback through the KRAS/ERK signaling pathway between the membrane and the cell nucleus (as shown in the diagram).

Behavior of stem cells at high and low levels of miR-142
EMBL / Hanna Sladitschek

The results obtained explain how stem cells manage to maintain a pluripotent reservoir in conditions of changing concentrations of differentiation factors. This is fundamentally important for regenerative cell medicine, since undifferentiating cells can eventually develop into a malignant tumor.

microRNAs are small RNA molecules that do not directly participate in protein synthesis on the DNA matrix, but serve as an important regulator of post–transcriptional gene expression.

Portal "Eternal youth" http://vechnayamolodost.ru  09.03.2016