Partial reprogramming of the rejuvenated human cells for five years

American scientists have tested the technology of partial reprogramming in human cells and mice. They found that 2-4 days of the reprogramming factors shift the expression of genes so that cells from older donors have become closer to cells from young donors. However, their epigenetic age is also reduced. In addition, with the help of reprogramming managed to draw and functional defects in the cells of human cartilage and murine muscles. A study published in the journal Nature Communications.

The technology of reprogramming cells, that is, the return to the embryonic state known for almost 15 years. It is to one way or another start in the cells of the four transcription factors (Yamanaka factors) that switch off the genes associated with the specialization of cells, and it turns into an embryonic stem — that is, becoming a universal precursor for all cell types.

Aging is accompanied by a depletion of stem cells in the body, but those cells that are not able to share, lose part of their functions. So the idea of rejuvenation through the reprogramming. Not to turn tissue into embryonic stem cells, scientists are trying to use partial reprogramming, i.e. “turn on” the work of Yamanaka factors for a short time. To achieve this on mice, researchers genetically altered animals in which the expression of Yamanaka factors could be controlled by adding to the feed of a certain drug. And it turned out that the reprogramming is partially rejuvenates: the rapidly aging mice and were able to extend their life.

But with man it is impossible to pull off. Not only because no one dares to bring transgenic people, but also because a mouse model of accelerated aging does not quite repeat the human disease, and they, in turn, does not fully correspond to normal aging. Therefore, if we want to use partial reprogramming to extend human life, you must learn to apply this technology to normal human cells.

For it took a team of scientists under the leadership of Thomas Rendo (Thomas Rando) from the Medical school of Stanford University. In his previous works researchers have devised a reprogramming Protocol that does not require integration of foreign genes into DNA — they just regularly introduced into the cells of RNA encoding the Yamanaka factors. After two weeks of this procedure, the cells become embryonic. Thus, according to the researchers, approximately on the fifth day, the cells displayed characteristics of stem cells: it’s time they considered a point of no return.

To achieve partial reprogramming, they injected the RNA of the Yamanaka factors during the four days in fibroblasts and endothelial cells (blood vessels) of a person. For this experiment, they used cells of elderly (60-90 years old) donor, and then compared gene expression in reprogramming cells with the cells of young (25-35 years) donors. The expression profile reprogrammable cells was closer to young than to old donors. At the same time, in reprogramming cells, researchers have found markers of stem cells means that they have not lost their focus.

The researchers then checked whether the reprogramming is associated with rejuvenation. To do this, they measured the epigenetic age of the cells before and after reprogramming and found that the fibroblasts of older donors have become younger on average by 1.84 years, and endothelial cells — on 4,94. Along with this came other signs of cell youth: it has become more of proteasomes and autophagosome machines intracellular “housekeeping” (p < 0.01), and endothelial cells have less Pro-inflammatory molecules.

The technique the researchers tested on other cell types. For example, they isolated the cartilage cells in the joints of patients with osteoarthritis. After reprogramming in these cells decreased the expression of markers of inflammation and oxidative stress, they began to share more often and produce more energy (p < 0.05). Then scientists isolated stem cells from the muscles of older mice, in part they were reprogrammable and transplanted into the damaged muscle from other elderly mice. After that, the force of muscle contraction increased by one third, that is, stem cells have become more involved in the healing of damaged areas.

However, before experiments on humans this technology still have a lot of checks. Because even a partial rejuvenation of the cells is fraught with the acquisition of the ability to divide, researchers need to repeatedly confirm that as a result of their manipulation of the cells do not become neoplastic. In this work, the researchers measured the telomere length reprogramming cells and showed that they were not long, however, for safe application of reprogramming will need to determine whether the cells lose their basic properties and do not receive any new.

While the story of rejuvenation is just beginning to develop, the reprogramming technology has already been successfully used, for example, for the treatment of eye diseases. And recently reprogrammable cells was first hoisted in the heart of the patient. In addition, there are already ideas of how the reprogramming can help in case of infertility and the Huntington’s disease.

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