In collaboration with the University of Cambridge, Professor Shosei Yoshida of the Division of Germ Cell Biology at the National Institute for Basic Biology, Assistant Professor Yoshiaki Nakamura of the Graduate School of Integrated Life Sciences at Hiroshima University, and colleagues successfully controlled the fate of transplanted mouse spermatogonial stem cells, which dramatically improved tissue regeneration efficiency. In their experiment, normal mouse spermatogonial stem cells were transplanted into the testes of infertile mice that did not have spermatogonial stem cells, followed by tracking the fate of each cell. Results showed that only a small proportion of stem cells engrafted in the host maintained the function of stem cells responsible for tissue regeneration. Moreover, they found that the administration of an inhibitor of stem cell differentiation after the transplantation led to an increase in the number of stem cells and that the transplanted mice could produce offspring by natural mating.
These findings, published in the April 13 issue of the international scientific journal Cell Stem Cell, are expected to be useful for the recovery of the reproductive capacity damaged by chemotherapy in cancer treatment as well as for the conservation of genetic resources of rare animals.
Tissue stem cells maintain the normal function of many organs in multicellular animals through self-renewal and cell differentiation. The morphology and function of impaired tissue can be restored by the transplantation of tissue stem cells, including hematopoietic stem cell transplantation (bone marrow transplantation), which is a radical treatment for leukemia. Transplantation of spermatogonial stem cells, one type of tissue stem cell, was developed in mice in 1994, after which successful cases have been reported in domestic animals and monkeys. However, the transplantation efficiency of the spermatogonial stem cells has been exceedingly low. Thus, despite their normal function, the number of regenerated sperms has been small, and artificial insemination has been necessary for the production of offspring. In addition, the behaviors of the transplanted spermatogonial stem cells remained unknown.
In this study, the research group transplanted spermatogonial stem cells labeled with green fluorescent protein into infertile host mice treated with a drug to remove germ cells. Next, they tracked the fate of the transplanted spermatogonial stem cells from 2 to 180 days after transplantation, which was analyzed using a mathematical/statistical model.
The results showed that a large number of stem cells engrafted immediately after transplantation which was followed by self-renewal, differentiation, and cell death that occurred randomly. Conventionally, spermatogonial stem cells were thought to regenerate tissues efficiently after transplantation. However, most of the engrafted stem cells were found to disappear without self-renewal, while only about one-tenth of the stem cells achieved regeneration.
Therefore, the research group investigated whether the regeneration efficiency could be improved by manipulating the fate of transplanted stem cells. They temporarily administered host mice transplanted with stem cells with an inhibitor of their differentiation into spermatozoa (retinoic acid synthesis inhibitor).
This resulted in a 5- to 10-fold increase in the number of stem cells due to elevated self-renewal, and normal spermatogenesis was observed 90 days after transplantation. Furthermore, these mice produced healthy offspring by normal, natural mating.
These findings are also expected to be useful for understanding the mechanism underlying the effect of hematopoietic stem cells after bone marrow transplantation and for the recovery of fertility in males after chemotherapy for cancer.
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