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April 14, 2011

A plan for conducting research on differentiating human ES/iPS cells into germ cells

Kazutoshi Takahashi, a lecturer at the Center for iPS Cell Research and Application (CiRA), Kyoto University, and his colleagues have received a green light from the government to conduct a research on differentiating human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) into germ cells. The researchers at CiRA, where Dr. Shinya Yamanaka serves as director, hope that the research will contribute to the understanding of the mechanisms of infertility.

The research program titled "Establishment of Methods for Inducing Human ES/iPS Cells to Differentiate into Germ Cells" was submitted to the Ministry of Education, Culture, Sports, Science and Technology (MEXT), earlier this year and was approved on April 8, 2011. Likewise, an application for amendments to the ongoing program titled "Research on the Differentiation Capacity of Pluripotent Stem Cells Derived from Human ES Cells and Their Safety for Transplantation with a View to Establishing a New Treatment Method" in which human ES cells are used under the responsibility of Yamanaka, also got approval on March 9, 2011.

With the government approval, CiRA has started conducting the germ cell research using ES⁄iPS cells. The research is aimed at developing methods for inducing the differentiation of human ES⁄iPS cells into germ cells and will be carried out in cooperation with the group led by Professor R. R. Pera at Stanford University.

Purposes of the study
1) Optimization of the method for the in vitro induction of differentiation of human ES/iPS cells into germ cells
In the past studies on the induction of differentiation of human ES cells into germ cells, no mature normal germ cells have been obtained. The CiRA researchers will seek to establish appropriate as well as efficient differentiation methods in this research.

2) Establishment of methods for generating optimal iPS cells to induce germ cells
Various methods of generating iPS cells have been reported in the past few years. They have suggested that what kind of cells the generated iPS cells can differentiate into, or which tissue the generated iPS cells can convert to, differs according to the type of somatic cell, combinations of pluripotency–inducing factors, and kinds of vectors to introduce the factors into somatic cells. In this study, therefore, the researchers first will try to establish a method for selecting optimal iPS cell lines for differentiation of human iPS cells into germ cells.

It is believed that advancing research on the differentiation of both ES cells and iPS cells into germ cells will help build a research base to elucidate the etiology of infertility, to establish new methods for diagnosing, preventing and treating infertility, and to develop new drugs in the future as well.

Background of the research
It has been reported in the past that fetuses generated with the fertilization of germ cells derived from mouse ES cells came to full term, although they died immediately after birth. On the other hand, in a research using ES cells derived from cynomolgus monkeys, a kind of primates, it was reported that the gene marker linked with germ cells was slightly expressed when the induction of differentiation was attempted using multiple growth factors.

Although researches on differentiating human ES cells into germ cells have been carried out in foreign countries, the efficiency of differentiation is still low, and normal mature gametes have not been generated. A method to establish mature germ cells has yet to be developed. In addition, researchers need to examine whether iPS cells will differentiate into germ cells.

Conducting research on deriving ES/iPS cells into germ cells may provide us with knowledge of how germ cells are generated, which have been difficult to investigate until now. Some causes of infertility are hereditary. Generating iPS cells from somatic cells taken from various patients to investigate processes of their differentiation into sperms and eggs will elucidate causes of infertility attributable to germ cell damages, and substantially contribute to the development of drugs and treatment strategies in the future.

Bioethical issues
Generation of germ cells in vitro may lead to new ethical issues. The MEXT enforced on May 20, 2010, the "Guidelines for Research on the Germ Cell Generation from Human iPS Cells or Human Tissue Stem Cells (Germ Cell Guidelines)." The MEXT also amended on May 20, 2010, the "Guidelines for the Use of Human ES Cells." CiRA will conduct this research in strict compliance with these guidelines, and continue to discuss how to proceed it in a socially acceptable manner.

[Glossary]
Germ cells
Germ cells transfer hereditary information from one generation to the next. Human primordial germ cells undergo a very complex process including meiosis to become mature germ cells in the course of over ten years.

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