A rat gave birth to a mouse
Chimeric rats produced mouse spermatozoa
Vera Sysoeva, N+1
Scientists have created chimeric rats whose gamete–producing organs have been replaced with donor ones - from other rats and even mice. The gametes obtained in this way in chimeric rats carried either the genetic information set by scientists, or generally belonged to another species, and at the same time retained their viability and functions. Scientists hope that their proposed approach will become a convenient tool for genetic research, and maybe even save some endangered animal species from extinction. The work was published in Nature Communications (Kobayashi et al., Blastocyst complementation using Prdm14-deficient rats enables efficient germline transmission and generation of functional mouse spermatids in rats).
Genetically engineered animals allow scientists to study the functions of genes in the body and simulate hereditary human diseases. For example, using CRISPR/Cas9 gene editing technology, it is possible to create mosaic animals in which part of the cells will carry a given mutation, and part will not. You can also add an artificial mouse chromosome to the cells, which can carry several million pairs of nucleotides. An artificial mouse chromosome is often used to create humanized animal models, but inserts of this length cannot be obtained by conventional editing of embryos.
However, the modifications received by animals are sometimes not inherited or transmitted with poor efficiency, because the modified cells lose out in competition to the cells of the host animal. Therefore, scientists working in this field have been looking for an experimental approach for some time that would allow them to grow animals with viable germ cells carrying the specified mutations.
There is also a technology when stem cells of one animal (donor) they are planted in another embryo with a mutation that does not allow any organ to develop. As a result, in the second animal (the host), this organ develops from stem cells provided to the embryo. For example, in this way you can even create rats that will form mouse kidneys, or vice versa, mice with rat organs. If chimeric animals with mutation-bearing sex glands (gonads: testes and ovaries) were obtained in the same way, then the germ cells in such animals would transmit the necessary genetic information to the offspring.
Biologists from the Japanese National Institute of Physiological Sciences, led by Masumi Hirabayashi, managed to grow gonads in rats with a missing gene Prdm14, which is responsible for the development of these organs in animals.
First, scientists tested whether knockout of the Prdm14 gene would ensure the development of gonads in embryos only from donor stem cells. To do this, stem cells carrying the red fluorescence gene were implanted into blastocysts (embryos at an early stage of development) of rats with knockout Prdm14, and were injected into mother rats. The experiment was successful: the cells of the sex glands in the resulting rats had red fluorescence. There were no host animal cells in these organs.
Next, the scientists tested whether it was possible to breed offspring with an additional artificial chromosome using this method. By analogy with the previous experiment, the researchers added stem cells carrying an artificial mouse chromosome to the Prdm14 knockout blastocysts. The reporter gene on the chromosome was the green fluorescence gene. Thus, it was possible to obtain rats in which gonads produced germ cells with an artificial mouse chromosome. By crossing these animals, the authors of the work received offspring whose artificial chromosome was already in all cells of the body.
The scheme of the experiment. Figure from the press release of the National Institute for Physiological Sciences Mouse sperm generated in rats – VM.
In the same way, scientists created chimeric rats with mouse sex glands by adding mouse stem cells to rat blastocysts. The spermatozoa produced by animals did not move well, but they turned out to be functional. The researchers managed to artificially fertilize ordinary mice with these cells and get healthy offspring. Almost half of the mice had fluorescence, which is consistent with the Mendelian distribution.
Mice obtained by fertilizing ordinary mice with spermatozoa produced by rats with mouse testicles. As expected, according to the Mendelian distribution, about half of the mice have fluorescence. A drawing from an article by Kobayashi et al.
The authors of the work have shown that it is possible to create chimeric animals with sex glands developed from stem cells of an animal of another species. The researchers suggest that this technology will find application not only as a tool for basic research: they hope that in this way it will be possible to maintain the number of species threatened with extinction. It will be enough to grow the sex glands of these animals in other host animals and cross them.
Such a technology – the cultivation of animal organs of another species in the host animal - can find application in medicine. Perhaps someday human organs for transplantation will be grown in chimeric pigs or monkeys. Despite all the ethical issues associated with this approach, and the prohibitions that in some countries are imposed on research in this area, people's attitude to the idea of chimera organs seems to be gradually changing towards approval.
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