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A group of scientists have reported the creation of functioning sperm-like cells from mouse embryonic stem cells, and publish their research in the journal Cell Stem Cell. The team report that these cells were able to produce viable offspring in when injected into egg cells and implanted in the mice.
Prof. Robin Lovell-Badge, Group Leader, The Francis Crick Institute, said:
“I expect many women think it is easy to make sperm. Most men just sit there and make millions of the little blighters every hour. However, as this paper clearly shows, it is much more complex than this. It requires a complex orchestration of factors and probably cell-cell interactions over time and space to go from early, or primordial germ cells (PGCs) through multiple stages, including changes in cell shape, and special cell divisions, notably those of meiosis that reduce chromosome copy number from two (diploid) to one (haploid) and eventually end up with spermatids and then sperm.
“It would be fantastically useful for basic research, but also potentially a way to allow men who can’t make sperm, due to cancer treatments or infectious diseases (such as mumps), to have children if it was possible to derive sperm, or at least spermatids that can be used to fertilise eggs by intracytoplasmic sperm injection (ICSI) all the way in vitro from pluripotent stem cells (ES or iPS cells, where the latter could be derived from the patient).
“The first part, reliably getting PGCs, was solved in the mouse a few years ago. But to get them to reliably go any further, and to make spermatids or sperm able to fertilise eggs and give healthy pups required putting them into the testes of young mice. It was assumed that other (somatic) cells of the testis, and perhaps also systemic factors such as hormones, were required to control the differentiation of the PGCs into spermatogonial stem cells and then to allow these to go along the complex path to make sperm.
“This paper by Zhou and colleagues shows that this is indeed the case. By providing somatic cells from testes of newborn mice devoid of their own germ cells, and various factors and hormones in the medium, they show that ES cell-derived PGCs can go all the way through meiosis and give rise to spermatids in vitro that are able to fertilise eggs after ICSI and give rise to healthy offspring. They have been very careful to check relevant details throughout the process, following a set of “gold standards” that were established to help the field progress. So this is an impressive amount of work and the results are exciting.
“However, many questions remain to be answered and there is scope to improve the methods. For example, the PGCs seem to go straight into meiosis rather than give rise to spermatogonial stem cells. Presumably the testicular cells fail to establish a proper stem cell niche in the cultures. This means that there is no expansion of germ cell numbers or continuous production of spermatids. The latter are also less efficient at giving offspring than spermatids isolated directly from testes, which suggests that not all of the germ cells are differentiating correctly. However, the fact that a significant number do, means that it will now be possible to tweak the culture conditions to discover how to better mimic the in vivo situation.”
Prof. Daniel Brison, Professor of Clinical Embryology and Stem Cell Biology, University of Manchester, said:
“This is a very exciting study showing the feasibility of producing functional male gametes in the laboratory. There are many technical obstacles before this technology could be applied to men, and the major issue is safety. There are already concerns that children produced by conventional assisted reproduction technologies using sperm produced normally in the body may be at risk of altered health outcomes (see New Scientist this week). Therefore before laboratory-made sperm could be used to produce children, extensive safety testing would have to be carried out. Nevertheless this appears to be a major scientific advance in meiosis research.”
Prof. Richard Sharpe, Group Leader of Male Reproductive Health Research Team, MRC Centre for Reproductive Health, University of Edinburgh, said:
“What is novel and exciting about this new study? The present study is a mammoth piece of work that must have taken many years. It has generated mouse immature sperm-like cells (spermatids) from embryonic stem cells (derived from mouse embryos) and shown that when these are injected into female eggs and then implanted into female recipient mice they develop into normally fertile offspring. What is new about this, is that the authors show good evidence for correct development of the germ cells and their DNA at each step along the way, which encourages the belief that ultimately this could be made to work in men.
“What does this mean for infertile men? Though this approach offers hope for the future, its application to men is a long way off, for three reasons:
“Background: Male infertility is common and in most cases there are no effective treatments. For some infertile men who produce (infertile) sperm, fertility may be rescued by assisted reproduction techniques involving injection of the sperm into the egg in the laboratory, followed by its implantation into the female partner. However, for men who fail to produce any sperm, there are no effective treatments; their only recourse is to use donor sperm. Researchers have tried for decades to generate sperm in the laboratory so as to open up the possibility of restoring fertility to infertile men. There have been numerous claims for success down the years, but none have proved to be reproducible, although there has been some success in generating mouse sperm. Why is it so difficult? Each sperm takes 10 weeks to make and must go through a sequence of major changes, for example halving the number of chromosomes (from 46 to 23), if it is to be normally fertile. To engineer this in the laboratory is a huge challenge.”
Prof. Azim Surani, Director of Germline and Epigenomics Research, The Gurdon Institute, University of Cambridge, said:
“This research is potentially interesting but requires independent verification. There are some surprising elements, such as the highly accelerated rate of development of spermatid-like cells in culture, and the absence of spermatogonial stem cells, indicating that the ‘developmental timer’ is awry.
“It also remains to be seen if this protocol could work with human stem cells because of the known differences between the mouse and human germline, and the protracted nature of human germline development.”
Prof. Allan Pacey, Professor of Andrology, University of Sheffield, said:
“This is an interesting study which represents a further step forward in our abilities to produce sperm outside the body in a laboratory dish. This would be a remarkable thing to be able to do, both for the advancement of science and also to be able to help infertile men father children that are genetically theirs. But no-one has managed to do this yet.
“One of the major concerns about lab-made sperm is whether or not they are genetically the same as healthy sperm produced in the body. Therefore it’s reassuring to see that the scientists in this study have paid very careful attention to this and their results appear to show that the sperm-like cells they have made are genetically normal.
“However, it’s important to note that the sperm-like cells produced in the study were not fully mature sperm as we might know them. They appear to be early sperm cells called spermatids. These contain the same genetic material that fully formed sperm do, but they do not have the ability to swim as the sperm tail is not yet formed properly. So in order to fertilise they must be injected into an egg in the same way that an embryologist does when performing ICSI as part of IVF.
“Therefore, in spite of these encouraging results, we are still some way from immediately applying this technique as a potential cure for human male infertility. Moreover, in their experiments the authors used embryonic stem cells as their starting material. But to make sperm for infertile men, it would probably be necessary to use an adult cell from some part of their body.
“Therefore, it remains to be seen if this technique could be applied in humans to create sperm-like cells that might be useable in IVF. That needs further work and I hope someone already has this underway.”
Prof. Chris Barratt, Professor of Reproductive Medicine, University of Dundee, said:
“There have been numerous attempts (and false dawns) to developing a robust system for in vitro meiosis. A number of studies have been published that have subsequently been difficult to repeat. This has led to the scientific community establishing a series of sentinel markers that need to be established to determine the fidelity of meiosis in vitro. This is a landmark study in that it has satisfied these internationally agreed standards.
“Importantly although the efficiency of the process remains to be improved the authors (using ICSI) achieve live births that are themselves fertile.
“Whilst human work is some way off it is closer than we think. The reason – although spermatid injection in the UK is currently illegal, very recently work1 from Japan by Yanagimachi and colleagues has reportedly achieved healthy live babies using round spermatid injection, a similar stage of spermatogenetic cells as reported in this paper (spermatid like cells).”
1 http://www.ncbi.nlm.nih.gov/pubmed/26575628
Prof. Darren Griffin, Professor of Genetics, University of Kent, said:
“The paper, using mice, represents some excellent science in understanding the basis of meiosis – the process that drives genetics – and the work is exciting and well performed. However, we need to exercise a note of caution when considering it as a possible treatment option for infertile men sometime in the future. While the work is undoubtedly a significant step towards that goal, there are issues of reproducibility and safety in a human system (which may be quite different and more complex than in mice) that need to be addressed.”
Prof. Harry Moore, Professor of Reproductive Biology, University of Sheffield, said:
“It is impressive to mimic different stages of sperm development in vitro and take the cells through meiosis to the spermatid stage especially as spermatogenesis is so sensitive to peptide and steroid hormone levels. To achieve offspring after ICSI clearly shows the developmental capacity of the spermatids (immature post-meiotic sperm cells) although perhaps the result is not so extraordinary as intrinsic development of germ cells in vitro was demonstrated in mice by Geijsen et al more than a decade ago (2004).
“My lab demonstrated human spermatid development from human embryonic stem cells in 2009 but to very low efficiency and of course developmental potential could not be determined (Hum Reprod. 2009 Dec;24(12):3150-9)1. Indeed, even if in the mouse the germ cells undergo meiosis correctly and epigenetic marks are established as indicated in this paper, we do not know if this process will be safe for humans. Therefore there is much further research required.
“The derivation in vitro of self-renewing human spermatogonial stem cells (SSCs) from iPS cells which can be transplanted back to the testis may a more feasible and safer route to restore fertility in boys/men that have lost these cells and are otherwise totally infertile. In this case full mature sperm development might be restored in the testis reducing risks of genetic defects which might be incurred in vitro, which has been suggested but not yet demonstrated (i.e Regen Med. 2013 Sep;8(5):523-5. doi: 10.2217/rme.13.57. Will it be possible to restore sperm production after childhood cancer treatment? Pacey AA, Moore HD.)2.”
1 http://www.ncbi.nlm.nih.gov/pubmed/19770126
2 http://www.ncbi.nlm.nih.gov/pubmed/23998745
Prof. Simon Fishel, Founder & President, CARE Fertility Group, said:
“This is exciting research that may represent a possible avenue in the longer term for male infertility. However, establishing safety along with reproducibility will be key before it can be considered as an option for clinical practice, but one can only encourage an acceleration of further important studies in this area, whilst congratulating the authors on their work to date.
“We do have therapies today for most male factor conditions offering men the chance of their own genetic child. However in those few conditions when we cannot acquire sperm cells to inject into the egg – such as failure in the manufacturing process – this remains an intractable problem for men wanting their own genetic child. This study was done using mice and with embryonic stem cells; it remains to be understood how embryonic stem cells could be used to aid the above mentioned clinical conditions. But it does open up prospects for further research.”
Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:
“Chinese scientists in this study were able to differentiate mouse embryonic stem cells (mESC) into fully functional spermatozoids in vitro. Spermatogenesis is a very complex biological process and for a long time it has been believed that it is impossible to recapitulate in vitro. Previously, specific segregation of chromosomes in germ cells (called meiosis) was achieved only in vivo by placing primordial germ cell-like cells, generated from either embryonic stem cells or induced pluripotent stem cells (iPSC), into mouse testes for several weeks. Zhou and colleagues have mimicked the in vivo testis environment by co-culture of mESC-derived primordial germ cell-like cells with cells suspension from mouse testes.
“Although the process is still not fully defined, because it requires the presence of other cells, the report is a significant achievement and major step forward to generation of gametes under fully defined conditions in vitro.
“Previously, using iPSC from azoospermic and fertile men, human spermatozoids were differentiated in vivo, in mouse testes1. However, the scientists were not able to follow all steps of meiosis and spermatogenesis. Following this method, we will be able to analyse germ cells at the different stages of differentiation and understand molecular mechanisms behind fertility disorders.”
1 http://www.ncbi.nlm.nih.gov/pubmed/24794432
‘Complete meiosis from embryonic stem cell-derived germ cells in vitro’ by Quan Zhou et al. published in Cell Stem Cell on Thursday 25 February 2016.
Declared interests
Prof. Robin Lovell-Badge: “I have full time employment as a Senior Group Leader at the Francis Crick Institute (at Mill Hill). I run a lab that studies sex determination and aspects of testis and ovary development mostly using mice as our experimental model, and with some work on the chick. We have some projects that are related to the topic of the Zhou et al paper, but indirectly. I am a member of the Hinxton Group, which explored the subject of in vitro derived gametes and published on this a few years ago. I am also a member of the Scientific and Clinical Advances Advisory Committee (SCAAC) for the HFEA. This pays a small honorarium based on actual hours spent in committee meetings. The topic of in vitro derived gametes is something we have discussed and will probably do so again. ”
Prof. Daniel Brison: “I have no conflict of interests to report.”
Prof. Richard Sharpe: “I’ve no conflicts to declare.”
Prof. Azim Surani: “I declare that I do not have any connections or associations that could affect my objective assessment of the work for which I have provided a quote.”
Prof. Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility and Trustee of the Progress Educational Trust (all unpaid). Also, recent work for the World Health Organisation, British Broadcasting Corporation, Purple Orchid Pharma (paid consultancy with all monies going to University of Sheffield). Co-applicant on a research grant from the Medical Research Council (ref: MR/M010473/1).”
Prof. Chris Barratt: “I have no commercial interests, shares etc. I am a paid employee of University of Dundee. I am a member of WHO committee for guidelines in fertility.”
Prof. Darren Griffin: “No conflict of interest.”
Prof. Harry Moore: “I declare I have no competing interests related to: paid employment or self-employment; grant funding; voluntary appointments; memberships; decision-making positions; other financial interest.”
Prof. Simon Fishel: “I am a shareholder in the CARE Fertility Group – no other conflicts but I am a Fellow of the Royal Society of Biology, a member of the British Fertility Soc, and of the Health Professions Council (as relevant to the UK).”
Dr Dusko Ilic: “I confirm that I have no conflict of interest.”