September 21, 2018

expert reaction to a study into generating human reproductive cells in vitro

Reactions to research published in Science that shows human reproductive cells can be produced in vitro.

Prof. Robin Lovell-Badge, Group Leader, The Francis Crick Institute, said:

“The paper by Yamashiro et al is another careful and valuable piece of research from Mitinori Saitou’s lab. There are many good reasons to want to derive functional eggs (oocytes) from human induced pluripotent stem cells (iPSCs) entirely in vitro. They would be valuable for research into the development of these special cells, and to understand how critical processes fail all too often (chromosome segregation during meiosis, etc).  They could be used to allow women who were rendered infertile as a result of treatments for childhood cancers to have their own genetically related children. They might allow the use of genome editing approaches to avoid genetic disease.

“Yamashiro have used knowledge gained in previous work on the mouse, where it was possible to combine mouse iPSC-derived primordial germ cell like cells (PGCLCs; the earliest stage of germ cell development before they have entered the developing gonads, where they will then start the process to make sperm if these are testes, or eggs if they are ovaries), with supporting cells from embryonic mouse ovaries. The latter, referred to as granulosa cells, combine with each of the early egg cells, oogonia, to form follicles, and once these are formed they help the oogonia to eventually develop into mature fully grown oocytes. There are many critical steps that have to occur in the developing eggs for these to be functional – capable of being fertilised and giving normal offspring. This was achieved in the mouse experiments.

“In the current paper, they have used similar conditions with human iPSC-derived PGCLCs, making use of mouse ovary cells to support their development. It took about four months of culture for the germ cells to reach the oogonia stage. This is much longer than it takes with mouse PGCLCs, which probably reflects at least in part the extended time required for oogonia to develop in embryonic human ovary. However, although the data is very encouraging and better than reported by others, the oogonia were not quite normal in that several processes that have to occur within them to eventually be able to give functional oocytes, namely epigenetic reprogramming and X-chromosome reactivation, were clearly incomplete. It will be interesting to know if this is because the mouse granulosa cells can’t fully support human germ cell development or if there are other aspects to the culture system that need tweaking. Experiments involving long term cultures like this are very challenging.

“Therefore, although they haven’t quite cracked the problem of getting mature human eggs in culture, the work is very encouraging and provides an exciting base for further work.”

Prof. Evelyn Telfer, School of Biological Science, The University of Edinburgh, said:

“This is a detailed study that makes a small but significant incremental progression towards producing human female germ cells from induced pluripotent stem cells.

“The cells that this group have produced appear oogonia-like and this is a very early stage of germ cell development. There is no indication from this study whether these cells are capable of developing into functional oocytes. The conditions required to progress to the next step in vitro are still unclear. Whilst this is an interesting technical advance the use of mouse somatic cells to support the development of human germ cells would be an impediment to any clinical application.

“There is still a long way to go to show that functional, developmentally competent human oocytes/follicles can be formed from induced pluripotent stem cells”

Prof. Azim Surani, Director of Germline and Epigenomics Research, The Gurdon Institute, University of Cambridge, said:

“This study is an essential encouraging next step for the development of female primordial germ cells in culture, reconstituting ~2.5 to ~ 7 weeks of germ cell development in embryos in utero.  The stage reached marks the beginning of pre-meiotic gametogenesis, but they are still far from functional mature human eggs. The adoption of methods from the previous work using mouse cells is not fully optimised for humans. In this study, it takes  ~120 days of culture, instead of  ~40 days for development of germ cells in utero, and only 1-2%  of the human cells survive and progress to the next stage of development.  Further work will be essential to improve the efficiency and the maturity of the human germ cell development in culture”

Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London Faculty of Life Sciences and Medicine, said:

“In the newest report from one of the world-leading laboratories in reconstitution of human gametogenesis in vitro, Mitinori Satou and his team have demonstrated that it is possible to mature human oogonia-like cells from induced pluripotent stem cells (iPSC) in vitro. The work is built on the previous knowledge gained from in vitro reconstituted mouse oogenesis.

“Although the ultimate goal of developing in vitro iPSC-derived developmentally competent human oocytes is still very far off, the step they achieved is very significant. They recreated for the first time in vitro one of most complex events during human gametogenesis – epigenetic reprogramming.

“However, to generate oogonia, the human iPSC-derived primordial germ cell-like cells had to be co-cultured with gonadal somatic cells, isolated from mouse embryos, and the nature of the signals governing the process remained largely unknown”

Declared interests

Prof. Robin Lovell-Badge: “I do not have any financial conflicts of interest in this work, nor do I collaborate with the Saitou group, although my lab is involved in some related experiments.”

Prof. Evelyn Telfer: “No interests to declare”

Prof. Azim Surani: “I have no conflict of interest”

Dr Dusko Ilic: “I declare no conflict of interest”