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ヒトの卵母細胞を人工的に成熟させることに成功：海外専門家コメント

エディンバラ大の研究グループは、ヒトの未熟な卵母細胞を、試験管内において最終段階まで成熟させることに成功したと報告した。マウスなどでは卵母細胞からの成熟にも、成熟させた卵子で個体を得ることにも成功していたが、ヒトの卵母細胞を成熟させるには4段階も必要で全く実現できていなかった。ただし、今回の手法でも成熟に至る確率は低く、得られた成熟卵子の形態や受精能についても検討する必要があるとのこと。論文は2月9日付のMolecular Human Reproductionに掲載。この件についての海外専門家コメント（原文）をお送りします。

論文リンク（抜粋）

Molecular Human Reproduction

Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system

https://academic.oup.com/molehr/advance-article/doi/10.1093/molehr/gay002/4829657

Prof. Adam Balen

Professor of Reproductive Medicine and Surgery,Leeds Centre for Reproductive Medicine

原文 

“This is a very important and exciting study, confirming for the first time that human oocytes (eggs) can be cultured in the laboratory from strips of ovarian tissue. The application of this technology in the future would be for women and potentially also young girls, who require fertility preservation by the freezing of ovarian tissue and for whom it may not be feasible or appropriate to re-implant the ovarian tissue at a later date. Until now the freezing of ovarian tissue prior to chemotherapy for certain malignancies has required subsequent re-implantation after the disease is in remission – a procedure which in recent years has resulted in several births around the world – however this is only feasible if there is no risk of reintroducing the disease which required the sterilising chemotherapy in the first place.”

Prof. Azim Surani

Director of Germline and Epigenomics Research, The Gurdon Institute, University of Cambridge

原文

"The results reported in the study are interesting but much additional work is needed before concluding that they have the potential to be used in clinics. Molecular characterisation and chromosomal analysis is needed to show how these egg cells compare with normal eggs. These eggs are smaller than normal since the extruded polar bodies during maturation are much larger than normal. It might be of interest to test the developmental potential of these eggs in culture to blastocyst stage, by attempting IVF or ICSI. Additional analysis might also show if their experimental model could be useful for advancing knowledge of development of very early human eggs".

Dr Channa Jayasena

Society for Endocrinology member and Clinical Senior Lecturer at Imperial College London

原文 

“Only mature eggs can be fertilised into a baby. This is an elegant piece of work, demonstrating for the first time that human eggs can be grown to maturity in a laboratory. It would take several years to translate this into a therapy. However, this is an important breakthrough, which could offer hope to women with infertility in the future.”
 

Mr Stuart Lavery

Consultant Gynaecologist, Department of Reproductive Medicine, Hammersmith Hospital

原文 

 

“This work by the Edinburgh team represents a genuine step forward in our understanding of the final stages of human egg maturation in the laboratory. Telfer and her colleagues have succeeded where many other teams have failed, in growing human eggs from the earliest storage stage to full maturity- ready to be fertilised by sperm.  Although still in small numbers and requiring optimisation, this preliminary work offers hope for patients ahead of sterilising treatments such as chemotherapy, that they will be able to be parents later in life using this technology for fertility preservation.”

Prof. Robin Lovell-Badge

Group Leader, The Francis Crick Institute

原文 

 

“This paper claims to have developed a method for growing and maturing human oocytes (eggs) within primordial follicles (obtained from biopsies of ovaries) all the way through to oocytes that might be capable of being fertilised (metaphase II, or MII). This had been done previously only in the mouse, with the first demonstration some 20 years ago, and with substantial improvements made in following years. 

 

“Several of the steps had already been achieved by several labs with human material, notably going from primordial follicles to secondary (multi-laminar) follicles and from secondary follicles to MII oocytes, so the novel aspect of this current work is to have joined these into one continuous process. 

 

“However, there are several problems. It was really quite inefficient, with an unknown number of early follicles giving 87 secondary follicles of which only 9 gave rise eventually to mature fully-grown MII oocytes.  The pieces of ovarian tissue that they begin with contain some follicles that have already begun to develop, and the authors can’t be certain that the ones that did make it to fully-grown MII oocytes actually arose from primordial follicles – they could have developed from “primary follicles” or even some secondary oocytes present in the original tissue. The timing from beginning to end was also relatively fast compared to what is thought to happen in vivo, which could suggest that the mature oocytes were indeed not coming from primordial follicles. If the development was too fast, then this might lead to abnormal oocytes. 

 

“The characterisation of the oocytes obtained was rather minimal, but did indicate that they were not quite right. Usually, when the fully-grown oocyte divides to give rise to an MII oocyte, this is a very asymmetric cell division producing the large oocyte and a very small “first polar body”. The latter contains a nucleus, but has too little cytoplasm to support its survival for long. However, the “polar bodies” associated with the MII oocytes in this paper were very large. (The first meiotic cell division had not been sufficiently asymmetric.) In addition to suggesting that the oocytes had not developed normally, these large polar bodies could probably survive for longer and may even be capable of being fertilised. If both the oocyte and the polar body are fertilised (by separate sperm) this can lead to the development of a mosaic individual, composed of cells with two distinct genotypes.  

 

“Finally, for clarification, this work is not describing the development of mature oocytes all the way from pluripotent stem cells in vitro. It is beginning with small oocytes that are already enclosed in follicles that have been obtained from adult ovaries. In this respect it is also not clear whether the methods will be of use for the purpose of allowing fertility preservation from stored ovarian tissue obtained from girls prior to cancer treatments, which is one of the main justifications. The follicles in pre-pubertal ovaries will be at an early stage and perhaps quite different from those in an adult. 

 

Therefore, while this work may contain an important step, many more will have to be taken to reach the destination. But you cant make an omelette without breaking eggs.”

Dr Ali Abbara

Society for Endocrinology member and Senior Clinical Lecturer in Endocrinology at Imperial College London

原文 

“This exciting research is promising in that it suggests that we may be able to grow eggs from ovarian tissue, all the way from early stages to later development stages, ready for fertilisation by sperm; and that this process could be achieved outside of the human body. However, the technology remains at an early stage, and much more work is needed to make sure that the technique is safe and optimised before we ascertain whether these eggs remain normal during the process, and can be fertilised to form embryos that could lead to healthy babies. Still, this early data suggests that this may well be feasible in the future."

Prof. Ying Cheong

Professor of Reproductive Medicine, University of Southampton

原文 

“McLaughlin et al have successfully shown in their research, growth of eggs from the immature to the mature stage, where 9 out of 48 eggs cultured became ready for fertilisation in their laboratory. This research represents an important scientific advancement; given that gametes are very sensitive to the environment they grow in, and whilst the laboratory environment is carefully controlled, much of the in vivo environment within the reproductive tract is still unknown. Clearly, work has to be done to further our understanding on the fertilisation and development potential of these eggs.”

Prof. Darren Griffin

Professor of Genetics, University of Kent

原文 

 

“This is an impressive technical achievement using an approach that is commonly adopted for animal in-vitro embryo production, but thus far has proved more tricky in humans.  Part of the reason for this, it that in e.g. pigs and mice, large amounts of ovarian tissue can be used from killed animals (e.g. abattoir material) whereas in humans a small biopsy needs to be taken without compromising the health of the patient.  The main “selling point” of this paper is that, in the past, the authors have been successful in developing two stages of the process through which ovary material can be taken and an egg ready for fertilization can be produced. Here, they have, through meticulous experimentation, worked out how to complete the third and final stage.  This is all proof of principle and small numbers at this stage but the signs are good.

 

If routine, it would potential applications for banking of material e.g. in cancer patients, for improving fertility treatment, for in-vitro embryo production in non human animals (e.g. pigs and cattle) and for understanding the basic biology of this fundamental process. 

 

The press release accurately reflects the science, this is certainly good quality research backed up by solid data. In some ways it is incremental work from an already well respected group but it has not been done before in quite this way. The development of the “3^rd stage” is significant. 

It will be a while until this is implemented in the clinic but, if and when it is, this will be seen as one of the seminal advances.”

Prof. Simon Fishel

Founder and President and Head of R&D, and Professor of Human Reproduction, CARE Fertility Group

原文 

“The press release is perhaps more encouraging than the science or the authors promulgate. As has been seen in many attempts to develop human gametes in vitro over the years, what looks normal may not indeed be what we call 'developmentally competent', or indeed healthy. 

 

“The authors are scientist of the highest calibre and who have been engaged in this area of research for many years, which is why themselves they state that although they have developed egg cells in vitro, this has occurred with low efficiency and do not appear normal, with respect to what is called the 'Polar Body' – an important tiny adjacent cell released by a normal egg undergoing the process of maturation. Every one of the small number of eggs produced had an unusually large Polar Body. When we see large polar bodies in eggs from routine IVF cases this is indicative of a potentially abnormal egg. 

 

“To state "the most clinically significant aspect of this work is Fertility Preservation" is a highly premature comment given that no normal eggs have yet been shown to be developed by this inefficient method. 

 

“To continue to research in this area is indeed of importance for the very reasons state, that is, the need to have successful approaches to fertility preservation. So far only mice have been produced by growing eggs in follicles developed in vitro – this study demonstrates that there is much laboratory research to be undertaken still before we can be encouraged to believe that we will achieve healthy normal eggs for clinical purposes from in vitro developed follicles derived from human ovarian cortical tissue.”

Prof. Daniel Brison

Honorary Professor of Clinical Embryology and Stem Cell Biology; Scientific Director of the Department of Reproductive Medicine, University of Manchester

原文 

“This is an exciting breakthrough which shows for the first time that complete development of human eggs in the laboratory is possible, more than 20 years after this was achieved in mice.  As the authors acknowledge, there is much more important research still to do, but this could pave the way for fertility preservation in women and girls with a wider variety of cancers than is possible using existing methods.” 

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