Mice are not afraid of a heart attack
Reprogramming of cells partially restored the heart of mice after a heart attack
Polina Loseva, N+1
Scientists helped mice to restore heart muscle after a heart attack – this time by reprogramming, forcing cardiomyocytes to "rejuvenate" and begin to divide. It turned out that it is possible to avoid the formation of tumors and the effect is stronger the earlier treatment begins (ideally, even before the heart attack). The method cannot yet be applied to humans – mice have to be genetically modified for this. The work was published in the journal Science (Chen et al., Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice).
Many mammalian tissues regenerate very poorly, and the older the animal, the worse. This prevents internal organs from recovering from injuries and accelerates the aging of the body. Theoretically, it is possible to cope with this problem with the help of stem cells – but they can not always be obtained in the right quantities, they can be difficult to introduce into the lesion and, moreover, they do not always take root well.
Another option is to create stem cells on the spot, right inside the damaged tissue, or at least teach adult cells to divide. This can be achieved with the help of cell reprogramming technology: to introduce four transcription factor proteins into them (they are also called 4F, OSKM - by the names of proteins or Yamanaki cocktail – by the name of the discoverer), which force the DNA in the cell to repackage. At the same time, areas with many genes that work in young cells are unwound and become available for reading. And the cells themselves can acquire some of the properties of stem cells.
Recently, with the help of a similar technology, scientists partially restored the mice's vision after an eye injury. And now a group of researchers led by Thomas Braun from the Max Planck Society's Institute for Heart and Lung Research has taken up heart regeneration.
To deliver Yamanaka proteins to the heart, scientists had to use transgenic mice – the researchers embedded the genes of these four proteins in their DNA, but so that they worked only in cardiomyocytes (contractile cells of the heart muscle) and only in the presence of the antibiotic doxycycline.
The authors of the work gave the mice water with doxycycline constantly, and during the first six days the animals did not differ from the control ones, and then the changes began. In their cardiomyocytes, the production of contractile proteins increased, and cardiac output decreased – this meant that some kind of restructuring processes were taking place in the heart. In animals that were stopped receiving doxycycline at that moment, the heart quickly returned to normal work, that is, the process turned out to be reversible.
Those who continued to trigger the expression of Yamanaki proteins began to get sick after the 12th day and died quickly, even if doxycycline was canceled. At the autopsy, they found tumors in the heart tissue. Moreover, cells from these tumors took root in early mouse embryos – this is the criterion that allows them to be attributed to embryonic stem cells. Thus, the authors of the work confirmed that their technology allows for complete reprogramming of cells in vivo.
In order to heal wounds, complete reprogramming is not necessary and even dangerous. But partial reprogramming, which occurs in the first days of the action of doxycycline, can be useful – at the same time, the cells, as the researchers noticed at the beginning of the experiment, do not lose their specialization, but acquire the ability to divide.
To check how much this affects regeneration, the authors of the work tested their method on a model of a heart attack. They bandaged the anterior descending artery in mice, thereby interrupting the blood supply to part of the myocardium – and the animals were given doxycycline before a heart attack (6 days before), immediately after a heart attack, the next day or 6 days after (simulating maintenance therapy). It turned out that the latter option does not have a serious effect on the work of the heart (although it reduces the size of the scar on the muscle). But the first two allow you to partially restore muscle function, and prevention works noticeably better than therapy after a heart attack – perhaps also because young cardiomyocytes are more resistant to damage than older ones.
Myocardial recovery after a heart attack. Red is healthy tissue, blue is a fibrous scar. Rows from top to bottom: control, doxycycline before a heart attack, immediately after and 6 days after. Figure from the article by Chen et al.
Researchers believe that such technology can be used for other organs that regenerate poorly in the human body. But, since it will not be possible to genetically modify it in the near future, it will be necessary to master ways to start the expression of Yamanaka proteins from the outside – for example, through a viral vector. But so far, such experiments have been performed only on cell cultures in vitro – and in order to transfer them to living people, you will need to learn how to accurately control reprogramming and prevent the formation of tumors.
And we talked about how partial reprogramming can be used to rejuvenate the body as a whole and why Jeff Bezos and Yuri Milner recently invested in it in the text "Plans for old age".
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