Building tomorrow’s in vitro-derived germ cells on today’s solid facts

Building tomorrow’s in vitro-derived germ cells on today’s solid facts Molecular Human Reproduction (MHR) prides itself on innovation and has been delivering fresh initiatives in the 22 years since its inception. Under the guidance of the 2015–2018 editorial team of Christopher Barratt (Editor-in-Chief) and Michele Boiani (Deputy Editor), MHR has given impetus to themed issues on topics such as sperm competition, mitochondria, single cell analysis in development, microfluidics and embryo cleavage. As one further initiative, MHR launched a call for papers in the spring of 2017—the first in the journal’s history. The topic chosen ‘In vitro-generated germ cells—facts and possibilities’ (Boiani, 2017) was in recognition of the advances made in the field of in vitro gametogenesis and what implications it has for human reproduction. Briefly, this field was pioneered by Hübner and colleagues (2003) and reached a zenith by Zhou and colleagues (2016) and Hikabe and colleagues (2016) who demonstrated the generation of functional oocytes and spermatozoa from mouse stem cells in vitro. The call for papers returned numerous expressions of interest. Proposals for manuscripts were selected and invited for full submissions. Now that the call is closed and the manuscripts have been peer-reviewed and accepted for publication, we are proud to present the resultant collection. ‘In vitro-generated germ cells—facts and possibilities’ features nine articles, of which seven are research articles and two are reviews. In this editorial, we summarize them concisely, while highlighting their common thread. McLaughlin and colleagues (2018) present a multi-step culture system that allowed human ovarian follicles to grow from the earliest to the late follicular stages in 20 days, followed by oocyte in vitro maturation to metaphase II. This achievement is a crucial one towards making human oogenesis a tractable experimental system, and nears the prospects of making clinical use of the in vitro-grown oocytes. To complement this article in terms of male gametogenesis, Mincheva and colleagues (2018) present a culture system that supports testicular cell suspension from adult men, resulting in the organotypic reaggregation in seminiferous cord-like structures. This achievement is not only a ‘first time’ in the human species, but also a ‘first time’ of adult testes been used as starting cellular material. Although a proof of functionality was not in the scope of this work, we look forward to it. Among various requirements, these organotypic structures will have to be able to form a blood-testis barrier, as described by de Michele and colleagues (2018) for their long-term (up to 139 days) organotypic culture of human prepubertal testicular tissue. Other requirements will probably include a proper balance of hormones, growth factors and vitamins in the culture medium, as discussed by Rombaut and colleagues (2018). These chemical components will be even more decisive when the starting material is not from natural precursors (e.g. from a biopsy) but from reprogrammed cells, or when the aim is to have gametogenesis proceed to completion in vitro instead of using the body as natural incubator for partly mature (and potentially teratogenic) germ cells. Regarding starting material from testis biopsies, Dumont and colleagues (2017) show in the mouse model that the culture medium composition is critical for the balance of survival and death of natural germ cell precursors present in the biopsy, as revealed by protein microarray technology. Oblette and colleagues (2017) take the in vitro production system one step further, by showing that the mouse spermatozoa produced in cultured testicular biopsies are indistinguishable from their natural counterparts, as measured by ploidy, DNA fragmentation, chromatin condensation and the presence of oxidized guanine as mutagenesis marker. These results have been reported here for natural precursors but may also be achieved from stem cell lines as the starting material. We were glad that we could extend the papers collection to include the paper from Mishra and colleagues (2018) and the paper from Gomes-Fernandez and colleagues (2018). Mishra and colleagues review the approaches and the techniques available to derive gametes from patients’ somatic cells via reprogramming (SCNT, iPS). In order to determine how close these surrogates are to the natural counterparts, there is a need for reliable molecular markers. Gomes-Fernandez and colleagues (2018) provide the researcher with a toolbox of antibodies – validated on unique human fetal material - that identify the natural primordial germ cells reliably. This is a much-needed support for those studies in which human primordial germ cell-like cells are differentiated in vitro. In retrospect, ‘In vitro-generated germ cells—facts and possibilities’ was an ambitious undertaking, and yet the high profile of the authors who responded to the call speaks for the merit of the initiative. Most of the subtopics we had suggested were covered in the papers. Whilst the experimental generation of gametes from stem cell lines was not a suggestion of ours, the review by Hendriks and colleagues (2017) reported on a survey that was made to ascertain public acceptance of stem cell-derived gametes, should they be available today. Confronted with eight possible indications for stem cell-based fertility treatment, over 800 Dutch participants returned a response that puts safety and effectiveness first, before ethical considerations. While the possibilities of in vitro-generated germ cells are wide, they must build on solid facts. As this collection shows, only elucidation of the many still unknown aspects of gametogenesis and progress in the culture methods to maintain germ cells for long periods in vitro, suitable for the different stage-dependent requirements of gametogenesis, can secure the production of germ cells from stem cells in a safe and reliable option for humans. It is this quest for solid facts that links these nine papers together, and they provide a skeleton plan of how future in vitro-generated germ cells might be attainable in humans. We hope that these papers will be well received. We enjoyed and learnt much from the process of this call for papers, which would not have been possible without some ‘external’ help. Therefore we would like to renew our gratitude to the colleagues who assisted MHR on this call for papers: Prof. Evelyn Telfer, Prof. Melissa Pepling, Prof. Rabindranath De La Fuente and Prof. Stefan Schlatt and the Editorial Team of MHR. References Boiani M. Call for papers: in vitro-generated germ cells-facts and possibilities. Mol Hum Reprod  2017; 23: 1– 3. Google Scholar CrossRef Search ADS PubMed  de Michele F, Poels J, Giudice MG, De Smedt F, Ambroise J, Vermeulen M, Gruson D, Wyns C. In-vitro formation of the blood-testis barrier during long-term organotypic culture of human prepubertal tissue: comparison with a large cohort of pre/peripubertal boys. Mol Hum Reprod  2018; 24: 271– 282 Google Scholar CrossRef Search ADS   Dumont L, Chalmel F, Oblette A, Berby B, Rives A, Duchesne V, Rondanino C, Rives N. Evaluation of apoptotic- and autophagic-related protein expressions before and after IVM of fresh, slow-frozen and vitrified pre-pubertal mouse testicular tissue. Mol Hum Reprod  2017; 23: 738– 754. Google Scholar CrossRef Search ADS PubMed  Gomes Fernandes M, Bialecka M, Salvatori DCF, Chuva de Sousa Lopes SM. Characterization of migratory primordial germ cells in the aorta-gonad-mesonephros of a 4.5 week-old human embryo: a toolbox to evaluate in-vitro early gametogenesis. Mol Hum Reprod  2018; 00: 000– 000. Hendriks S, Dancet EAF, Vliegenthart R, Repping S. The acceptability of stem cell-based fertility treatments for different indications. Mol Hum Reprod  2017; 23: 855– 863. Google Scholar CrossRef Search ADS PubMed  Hikabe O, Hamazaki N, Nagamatsu G, Obata Y, Hirao Y, Hamada N, Shimamoto S, Imamura T, Nakashima K, Saitou M et al.  . Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature  2016; 539: 299– 303. Google Scholar CrossRef Search ADS PubMed  Hübner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, De La Fuente R, Wood J, Strauss JF 3rd, Boiani M, Schöler HR. Derivation of oocytes from mouse embryonic stem cells. Science  2003; 300: 1251– 1256. Google Scholar CrossRef Search ADS PubMed  McLaughlin M, Albertini DF, Wallace WHB, Anderson RA, Telfer EE. Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system. Mol Hum Reprod  2018; 24: 135– 142. Google Scholar CrossRef Search ADS PubMed  Mincheva M, Sandhowe-Klaverkamp R, Wistuba J, Redmann K, Stukenborg JB, Kliesch S, Schlatt S. Reassembly of adult human testicular cells: can testis cord-like structures be created in vitro? Mol Hum Reprod  2018; 24: 55– 63. Google Scholar CrossRef Search ADS PubMed  Mishra S, Kacin E, Stamatiadis P, Franck S, Van der Jeught M, Mertes H, Pennings G, De Sutter P, Sermon K, Heindryckx B et al.  . The role of the reprogramming method and pluripotency state in gamete differentiation from patient-specific human pluripotent stem cells. Mol Hum Reprod  2018; 24: 173– 184. Google Scholar CrossRef Search ADS PubMed  Oblette A, Rives N, Dumont L, Rives A, Verhaeghe F, Jumeau F, Rondanino C. Assessment of sperm nuclear quality after in vitro maturation of fresh or frozen/thawed mouse pre-pubertal testes. Mol Hum Reprod  2017; 23: 674– 684. Google Scholar CrossRef Search ADS PubMed  Rombaut C, Mertes H, Heindryckx B, Goossens E. Human in vitro spermatogenesis from pluripotent stem cells: in need of a stepwise differentiation protocol? Mol Hum Reprod  2018; 24: 47– 54. Google Scholar CrossRef Search ADS PubMed  Zhou Q, Wang M, Yuan Y, Wang X, Fu R, Wan H, Xie M, Liu M, Guo X, Zheng Y et al.  . Complete meiosis from embryonic stem cell-derived germ cells in vitro. Cell Stem Cell  2016; 18: 330– 340. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular Human Reproduction Oxford University Press

Building tomorrow’s in vitro-derived germ cells on today’s solid facts

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Publisher
Oxford University Press
Copyright
© The Author 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
1360-9947
eISSN
1460-2407
D.O.I.
10.1093/molehr/gay022
Publisher site
See Article on Publisher Site

Abstract

Molecular Human Reproduction (MHR) prides itself on innovation and has been delivering fresh initiatives in the 22 years since its inception. Under the guidance of the 2015–2018 editorial team of Christopher Barratt (Editor-in-Chief) and Michele Boiani (Deputy Editor), MHR has given impetus to themed issues on topics such as sperm competition, mitochondria, single cell analysis in development, microfluidics and embryo cleavage. As one further initiative, MHR launched a call for papers in the spring of 2017—the first in the journal’s history. The topic chosen ‘In vitro-generated germ cells—facts and possibilities’ (Boiani, 2017) was in recognition of the advances made in the field of in vitro gametogenesis and what implications it has for human reproduction. Briefly, this field was pioneered by Hübner and colleagues (2003) and reached a zenith by Zhou and colleagues (2016) and Hikabe and colleagues (2016) who demonstrated the generation of functional oocytes and spermatozoa from mouse stem cells in vitro. The call for papers returned numerous expressions of interest. Proposals for manuscripts were selected and invited for full submissions. Now that the call is closed and the manuscripts have been peer-reviewed and accepted for publication, we are proud to present the resultant collection. ‘In vitro-generated germ cells—facts and possibilities’ features nine articles, of which seven are research articles and two are reviews. In this editorial, we summarize them concisely, while highlighting their common thread. McLaughlin and colleagues (2018) present a multi-step culture system that allowed human ovarian follicles to grow from the earliest to the late follicular stages in 20 days, followed by oocyte in vitro maturation to metaphase II. This achievement is a crucial one towards making human oogenesis a tractable experimental system, and nears the prospects of making clinical use of the in vitro-grown oocytes. To complement this article in terms of male gametogenesis, Mincheva and colleagues (2018) present a culture system that supports testicular cell suspension from adult men, resulting in the organotypic reaggregation in seminiferous cord-like structures. This achievement is not only a ‘first time’ in the human species, but also a ‘first time’ of adult testes been used as starting cellular material. Although a proof of functionality was not in the scope of this work, we look forward to it. Among various requirements, these organotypic structures will have to be able to form a blood-testis barrier, as described by de Michele and colleagues (2018) for their long-term (up to 139 days) organotypic culture of human prepubertal testicular tissue. Other requirements will probably include a proper balance of hormones, growth factors and vitamins in the culture medium, as discussed by Rombaut and colleagues (2018). These chemical components will be even more decisive when the starting material is not from natural precursors (e.g. from a biopsy) but from reprogrammed cells, or when the aim is to have gametogenesis proceed to completion in vitro instead of using the body as natural incubator for partly mature (and potentially teratogenic) germ cells. Regarding starting material from testis biopsies, Dumont and colleagues (2017) show in the mouse model that the culture medium composition is critical for the balance of survival and death of natural germ cell precursors present in the biopsy, as revealed by protein microarray technology. Oblette and colleagues (2017) take the in vitro production system one step further, by showing that the mouse spermatozoa produced in cultured testicular biopsies are indistinguishable from their natural counterparts, as measured by ploidy, DNA fragmentation, chromatin condensation and the presence of oxidized guanine as mutagenesis marker. These results have been reported here for natural precursors but may also be achieved from stem cell lines as the starting material. We were glad that we could extend the papers collection to include the paper from Mishra and colleagues (2018) and the paper from Gomes-Fernandez and colleagues (2018). Mishra and colleagues review the approaches and the techniques available to derive gametes from patients’ somatic cells via reprogramming (SCNT, iPS). In order to determine how close these surrogates are to the natural counterparts, there is a need for reliable molecular markers. Gomes-Fernandez and colleagues (2018) provide the researcher with a toolbox of antibodies – validated on unique human fetal material - that identify the natural primordial germ cells reliably. This is a much-needed support for those studies in which human primordial germ cell-like cells are differentiated in vitro. In retrospect, ‘In vitro-generated germ cells—facts and possibilities’ was an ambitious undertaking, and yet the high profile of the authors who responded to the call speaks for the merit of the initiative. Most of the subtopics we had suggested were covered in the papers. Whilst the experimental generation of gametes from stem cell lines was not a suggestion of ours, the review by Hendriks and colleagues (2017) reported on a survey that was made to ascertain public acceptance of stem cell-derived gametes, should they be available today. Confronted with eight possible indications for stem cell-based fertility treatment, over 800 Dutch participants returned a response that puts safety and effectiveness first, before ethical considerations. While the possibilities of in vitro-generated germ cells are wide, they must build on solid facts. As this collection shows, only elucidation of the many still unknown aspects of gametogenesis and progress in the culture methods to maintain germ cells for long periods in vitro, suitable for the different stage-dependent requirements of gametogenesis, can secure the production of germ cells from stem cells in a safe and reliable option for humans. It is this quest for solid facts that links these nine papers together, and they provide a skeleton plan of how future in vitro-generated germ cells might be attainable in humans. We hope that these papers will be well received. We enjoyed and learnt much from the process of this call for papers, which would not have been possible without some ‘external’ help. Therefore we would like to renew our gratitude to the colleagues who assisted MHR on this call for papers: Prof. Evelyn Telfer, Prof. Melissa Pepling, Prof. Rabindranath De La Fuente and Prof. Stefan Schlatt and the Editorial Team of MHR. References Boiani M. Call for papers: in vitro-generated germ cells-facts and possibilities. Mol Hum Reprod  2017; 23: 1– 3. Google Scholar CrossRef Search ADS PubMed  de Michele F, Poels J, Giudice MG, De Smedt F, Ambroise J, Vermeulen M, Gruson D, Wyns C. In-vitro formation of the blood-testis barrier during long-term organotypic culture of human prepubertal tissue: comparison with a large cohort of pre/peripubertal boys. Mol Hum Reprod  2018; 24: 271– 282 Google Scholar CrossRef Search ADS   Dumont L, Chalmel F, Oblette A, Berby B, Rives A, Duchesne V, Rondanino C, Rives N. Evaluation of apoptotic- and autophagic-related protein expressions before and after IVM of fresh, slow-frozen and vitrified pre-pubertal mouse testicular tissue. Mol Hum Reprod  2017; 23: 738– 754. Google Scholar CrossRef Search ADS PubMed  Gomes Fernandes M, Bialecka M, Salvatori DCF, Chuva de Sousa Lopes SM. Characterization of migratory primordial germ cells in the aorta-gonad-mesonephros of a 4.5 week-old human embryo: a toolbox to evaluate in-vitro early gametogenesis. Mol Hum Reprod  2018; 00: 000– 000. Hendriks S, Dancet EAF, Vliegenthart R, Repping S. The acceptability of stem cell-based fertility treatments for different indications. Mol Hum Reprod  2017; 23: 855– 863. Google Scholar CrossRef Search ADS PubMed  Hikabe O, Hamazaki N, Nagamatsu G, Obata Y, Hirao Y, Hamada N, Shimamoto S, Imamura T, Nakashima K, Saitou M et al.  . Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature  2016; 539: 299– 303. Google Scholar CrossRef Search ADS PubMed  Hübner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, De La Fuente R, Wood J, Strauss JF 3rd, Boiani M, Schöler HR. Derivation of oocytes from mouse embryonic stem cells. Science  2003; 300: 1251– 1256. Google Scholar CrossRef Search ADS PubMed  McLaughlin M, Albertini DF, Wallace WHB, Anderson RA, Telfer EE. Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system. Mol Hum Reprod  2018; 24: 135– 142. Google Scholar CrossRef Search ADS PubMed  Mincheva M, Sandhowe-Klaverkamp R, Wistuba J, Redmann K, Stukenborg JB, Kliesch S, Schlatt S. Reassembly of adult human testicular cells: can testis cord-like structures be created in vitro? Mol Hum Reprod  2018; 24: 55– 63. Google Scholar CrossRef Search ADS PubMed  Mishra S, Kacin E, Stamatiadis P, Franck S, Van der Jeught M, Mertes H, Pennings G, De Sutter P, Sermon K, Heindryckx B et al.  . The role of the reprogramming method and pluripotency state in gamete differentiation from patient-specific human pluripotent stem cells. Mol Hum Reprod  2018; 24: 173– 184. Google Scholar CrossRef Search ADS PubMed  Oblette A, Rives N, Dumont L, Rives A, Verhaeghe F, Jumeau F, Rondanino C. Assessment of sperm nuclear quality after in vitro maturation of fresh or frozen/thawed mouse pre-pubertal testes. Mol Hum Reprod  2017; 23: 674– 684. Google Scholar CrossRef Search ADS PubMed  Rombaut C, Mertes H, Heindryckx B, Goossens E. Human in vitro spermatogenesis from pluripotent stem cells: in need of a stepwise differentiation protocol? Mol Hum Reprod  2018; 24: 47– 54. Google Scholar CrossRef Search ADS PubMed  Zhou Q, Wang M, Yuan Y, Wang X, Fu R, Wan H, Xie M, Liu M, Guo X, Zheng Y et al.  . Complete meiosis from embryonic stem cell-derived germ cells in vitro. Cell Stem Cell  2016; 18: 330– 340. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Molecular Human ReproductionOxford University Press

Published: May 10, 2018

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