The reason for rejection
The immune system has hostilely accepted mitochondrial mutations of stem cells
And the more mutations there are, the longer the cells are grown in the laboratory
Polina Loseva, "The Attic"
Reprogramming cells, that is, returning them to the embryonic state, allows you to grow any tissue for the patient, which theoretically should easily take root in the body. But in practice, transplants of reprogrammed stem cells are often rejected. Scientists from Germany and the USA have experimentally demonstrated that it's mitochondria: their DNA mutates more often than nuclear DNA under normal conditions, and reprogramming further accelerates this process. And mitochondrial mutations alone are enough for the immune system to identify their carriers as enemies.
Stem cells inside tissues hide, as a rule, in secluded places where they practically do not come into contact with the immune system, so that it does not undertake to fight them. If foreign stem cells are introduced into the body, the immune system can react aggressively – if not to the aliens themselves, then to their already more highly specialized descendants, who come out to replace the dead cells in damaged tissues. At first glance, it seems that it would be possible to solve this problem by growing their own stem cells for the patient. This can be achieved by reprogramming, that is, the transformation of adult cells into embryonic stem cells. Then, any necessary tissue can be grown from the reprogrammed cells, which will be genetically identical to the patient's tissues and, therefore, will not be rejected by immunity. However, practice shows that not everything is so simple: in some preclinical studies on mice, even their own reprogrammed cells caused rejection.
Researchers from Germany and the USA decided to find out what gives reprogrammed cells to immune surveillance. They suggested that changes in the mitochondrial DNA of these cells could be to blame. The fact is that this DNA mutates about 10-20 times more often than the nuclear genome of a cell, probably because the mitochondrial repair system, i.e. DNA repair, works worse than in the nucleus.
Proteins encoded by mitochondrial DNA can make up about 30% of all cellular proteins if the cell actively produces and spends energy, as happens, for example, in muscles. So the activity of mitochondria in cells does not go unnoticed by the immune system.
To test whether mutations in mitochondria are associated with an immune response to reprogrammed cells, scientists have created hybrid stem cells of mice. They took the nuclei from the cells of animals of one line and transplanted them into the eggs of animals of another line (this method is called nuclear transfer). The result was induced pluripotent stem cells (iPS cells) with nuclear DNA from one animal lineage, and mitochondrial DNA from another. At the same time, the mitochondria in the two lines differed by literally a couple of significant mutations.
The resulting hybrid stem cells were launched into the body of the first line of mice to give the immune system a chance to get acquainted with foreign mitochondrial proteins. A few days later, the scientists checked whether the immune cells reacted to the aliens. And so it turned out: the former attacked the latter.
Then the researchers wondered if the human immune system recognizes mitochondrial mutations. They selected 15 patients who were about to undergo kidney transplantation and compared their mitochondrial genome with the mitochondrial genome of their donors. In each pair of people, they found 1-12 differences in the sequence of mitochondrial DNA. Three months after the transplant, when the recipients' immunity should have already become familiar with the donor organ, the researchers took a blood sample from the patients and isolated immune cells from there. These cells recognized mitochondrial mutations characteristic of their donors well and attacked cells carrying these mutations, but did not react to cells with other nuclear DNA variants.
It is known that during reprogramming, there are more mutations in cells, probably due to the fact that the DNA in the cell is rearranged. The scientists tested whether this was true for mitochondrial DNA: they counted the number of mutations in "fresh" pluripotent cells immediately after reprogramming and continued to count their number for several weeks as the cells multiplied. And the further they went, the more mitochondrial mutations became in them. When these cells were injected into the body of mice, the immunity of the "old" mice resisted the "pluripotent invasion" even more desperately.
The same principle seems to apply to human cells: the more time has passed after reprogramming, the more mutations have appeared.
Despite the fact that the researchers did not dare to test them on humans, they assume that reprogrammed stem cells are capable of causing a serious immune response. Apparently, the fact is that mutant cells die pretty quickly inside the body from an immune attack. When cells are artificially propagated in the laboratory, they do not pass natural quality control and mutants accumulate among them, to which the body can subsequently react as strangers.
No acute rejection of stem cells has been detected among humans so far, however, the statistics are small: induced pluripotent stem cells are just undergoing their first clinical trials. But in the future, the authors of the article warn, this problem may become more acute and it will be necessary to carefully sort stem cells before transplanting them to a patient.
Article by Deuse et al. De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans is published in the journal Nature Biotechnology.
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