The "source of youth" of stem cells
The secret of the immortality of stem cells lies in their metabolism
(Recall that stem cells do not perform any specialized work, they only divide constantly, but their descendants can differentiate into cells of different working types.)
Obviously, the stem state is caused by the peculiarities of genetic tuning: some genes work, some do not, and such a spectrum of working and non-working genes is, in principle, very different from what can be found in ordinary cells. Usually here they talk about epigenetic mechanisms that monitor the availability of various DNA sites for cellular molecular machines. If DNA is available for reading mRNA from it, it means that the gene is active; if DNA is "archived", inaccessible to proteins, the gene is silent.
Genome archiving is performed by histone proteins, which, interacting with DNA, form chromatin. Special enzymes can attach or detach methyl groups from histones, and such modification causes compaction or, conversely, loosening of chromatin – which means that DNA in combination with histones becomes more or less accessible for molecular manipulation. Methylation of histones serves as one of their main epigenetic mechanisms of regulation of genetic activity.
The methyl groups themselves are the product of metabolic reactions. And now researchers from Rockefeller University (USA) came up with the idea that the metabolism of stem cells itself helps them stay in this state (Discovery links shift in metabolism to stem cell renewal). The peculiarity of their DNA is that almost all of it is available for reading, that is, if we accept the hypothesis of metabolism, some substances must constantly form in cells that would support chromatin in an "unarchived" form.
In laboratories, stem cells are cultured in various nutrient media. Bryce Carey and his colleagues noticed that mouse embryonic stem cells (if I may say so, the most immortal and the most "omnipotent", since they can give rise to absolutely any other type of cells) grow better on one medium, and worse on another. Better in this case means that the cells retained their stem properties longer, that they were better at self-renewal.
It turned out that the cells growing in a "good" environment did without the amino acid glutamine. It produces alpha-ketoglutarate, which, in turn, plays an important role in the Krebs cycle, or tricarboxylic acid cycle. This is the name of the most important stage of cellular respiration, that is, the splitting of biomolecules in order to obtain energy. On the other hand, the Krebs cycle also serves as a supplier of many precursor molecules, which are already sent to synthetic reactions. In short, it is the most important nodal station of cellular metabolism.
However, the role of alpha-ketoglutarate is not limited to one Krebs cycle. It has been shown to be involved in the regulation of chromatin methylation. And although the cells did not receive glutamine for the production of alpha-ketoglutarate, they still took it from somewhere, and in quite large quantities. It turned out that they simply blocked the reaction of the Krebs cycle, in which the glutamine derivative turned into something else. The excess accumulating alpha-ketoglutarate was sent to the enzymes involved in chromatin rearrangement – here it stimulated the reaction of histone purification from methyl groups and, as a consequence, DNA activation. Due to the fact that the Krebs cycle was deprived of this molecule, cell growth could slow down slightly – after all, the cycle, recall, plays an important energy role. But the cell could, thanks to such a metabolic trick, maintain "eternal youth", keeping the entire genome unpacked.
Of course, here we can say that it's all about genes and their regulation again: it's just that cells grew on a "good" medium that had a genetic block for the aforementioned reaction of the tricarboxylic acid cycle. But if alpha-ketoglutarate was added to cells that grew in a "bad" environment, then their ability to self-renew noticeably increased. In an article in Nature (Carey et al., Intracellular alfa-ketoglutarate maintains the pluripotency of embryonic stem cells), the authors write that they also managed to notice changes in the activity of some genes that occurred precisely due to the presence or absence of alpha-ketoglutarate in the medium.
Of course, it was known before that a stem cell is not a "thing in itself", that it listens to the environment and changes its properties due to external changes. However, in this case, it was possible to demonstrate how a not very complex chemical molecule from the outside can affect one of the fundamental properties of a stem cell – its inability to age while remaining potentially immortal. That is, through the nutrient medium, we can control the stem culture; by transplanting such cells into the body, we can influence them through metabolism, without resorting to complex genetic manipulations. Although, of course, it is impossible to do without such manipulations, and the metabolic control method, if it enters into medical and biological practice, will join a long line of methods of working with stem cells.
Portal "Eternal youth" http://vechnayamolodost.ru12.12.2014