Reproductive BioMedicine Online (2014) 29, 273
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
EDITORIAL
Germ cells from human embryonic stem cells? Embryonic stem cells (ESC) have been successfully induced to differentiate into germ cells in a number of animal species, and in some cases fertilisation has been achieved and liveborn offspring delivered (Hayashi et al., 2012; Nayernia et al., 2006; West et al., 2010; Zhao et al., 2009). To date, however, successful fertilisation and pregnancy have not been reported in humans. This failure is in part due to the significant and serious ethical objections to work of this kind, and major concerns about the short- and long-term health of offspring that may result from ESC-derived germ cells. In parallel with the debate concerning the “rightness” of research of this nature runs the basic scientific research required to determine whether it is indeed possible to create germ cells derived from human ESC. A study in this issue of Reproductive Biomedicine Online (Chen et al., 2014) describes a complex and time-consuming process that appears to allow harvesting of cells derived from human ESC that express the germ cell genes VASA and GDF9. The authors used granulosa cell co-culture or conditioned media to increase the yield of human ESC-derived cells expressing the SSEA1 marker of early germ cell differentiation, and then manually collected cell clusters that demonstrated intense Oct-4 eGFP fluorescence after extended culture of up to 42 days. These cells were positive for VASA and GDF9, showing that they were differentiating along the germ cell pathway, although markers of mature oocyte formation such as expression of the zona pellucida protein ZP3 were not highly expressed. Intriguingly, occasional “follicle-like structures” with intense eGFP fluorescence were observed amongst these cells. This report builds on several previous studies that have identified “follicle-like structures” derived from human ESC in culture (Lan et al., 2013), and moves closer to the derivation of mature oocytes. Because the developmental programme of these oocytes is so artificial, there is a high chance that the oocytes, and therefore any offspring, will have developmental defects. A considerable amount of work needs to be done to demonstrate unequivocally that germ cells derived from human ESC do not differ in their gene expression from natural human germ cells, and that embryos derived from these cells also exhibit growth and development, and epigenetic regulation, comparable with embryos derived from
normal human germ cells. These essential results must be available before any attempt is made to produce a human pregnancy. Even with this reassurance it may be that an attempt to produce an embryo from human ESC-derived cells would be prohibited because of the huge and potentially tragic implications of bringing an abnormal child into the world. Nevertheless, this work is important scientifically and may lead to a better understanding of the earlier stages of gamete and embryo development without ever leading to a pregnancy. It may therefore be of significant clinical benefit without being so ethically challenging.
References Chen, H.F., Jan, P.S., Kuo, H.C., Wu, F.C., Lan, C.W., Huang, M.C., Chien, C.L., Ho, H.N., 2014. Granulosa cells and retinoic acid cotreatment enrich potential germ cells from manually selected Oct4EGP expressing human embryonic stem cells. Reprod. Biomed. Online 29 (in this issue). Hayashi, K., Ogushi, S., Kurimoto, K., Shimamoto, S., Ohta, H., Saitou, M., 2012. Offspring from oocytes derived from in-vitro primordial germ cell-like cells in mice. Science 338, 971–975. Lan, C.W., Chen, M.J., Jan, P.S., Chen, H.F., Ho, H.N., 2013. Differentiation of human embryonic stem cells into functional ovarian granulose-like cells. J. Clin. Endocrinol. Metab. 98, 3713–3723. Nayernia, K., Nolte, J., Michelmann, H.W., Rathsack, K., Drusenheimer, N., Dev, A., Wulf, G., Ehrmann, I.E., Elliott, D.J., Okpanyi, V., Zechner, U., Haaf, T., Meinhardt, A., Engel, W., 2006. In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev. Cell 11, 125– 132. West, F.D., Terlouw, S.L., Kwon, D.J., Mumaw, J.L., Dhara, S.K., Hasen, K., Dobrinsky, J.R., Stice, S.L., 2010. Porcine induced pluripotent stem cells produce chimeric offspring. Stem Cells Dev. 19, 1211–1220. Zhao, X.-Y., Li, W., Lv, Z., Liu, L., Tong, M., Hai, T., Hao, J., Guo, C.-L., Ma, Q.-W., Wang, L., Zeng, F., Zhou, Q., 2009. iPS cells produce viable mice through tetraploid complementation. Nature 461, 86–90.
http://dx.doi.org/10.1016/j.rbmo.2014.07.004 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Bill Ledger E-mail address: offi[email protected]
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
EDITORIAL
Germ cells from human embryonic stem cells? Embryonic stem cells (ESC) have been successfully induced to differentiate into germ cells in a number of animal species, and in some cases fertilisation has been achieved and liveborn offspring delivered (Hayashi et al., 2012; Nayernia et al., 2006; West et al., 2010; Zhao et al., 2009). To date, however, successful fertilisation and pregnancy have not been reported in humans. This failure is in part due to the significant and serious ethical objections to work of this kind, and major concerns about the short- and long-term health of offspring that may result from ESC-derived germ cells. In parallel with the debate concerning the “rightness” of research of this nature runs the basic scientific research required to determine whether it is indeed possible to create germ cells derived from human ESC. A study in this issue of Reproductive Biomedicine Online (Chen et al., 2014) describes a complex and time-consuming process that appears to allow harvesting of cells derived from human ESC that express the germ cell genes VASA and GDF9. The authors used granulosa cell co-culture or conditioned media to increase the yield of human ESC-derived cells expressing the SSEA1 marker of early germ cell differentiation, and then manually collected cell clusters that demonstrated intense Oct-4 eGFP fluorescence after extended culture of up to 42 days. These cells were positive for VASA and GDF9, showing that they were differentiating along the germ cell pathway, although markers of mature oocyte formation such as expression of the zona pellucida protein ZP3 were not highly expressed. Intriguingly, occasional “follicle-like structures” with intense eGFP fluorescence were observed amongst these cells. This report builds on several previous studies that have identified “follicle-like structures” derived from human ESC in culture (Lan et al., 2013), and moves closer to the derivation of mature oocytes. Because the developmental programme of these oocytes is so artificial, there is a high chance that the oocytes, and therefore any offspring, will have developmental defects. A considerable amount of work needs to be done to demonstrate unequivocally that germ cells derived from human ESC do not differ in their gene expression from natural human germ cells, and that embryos derived from these cells also exhibit growth and development, and epigenetic regulation, comparable with embryos derived from
normal human germ cells. These essential results must be available before any attempt is made to produce a human pregnancy. Even with this reassurance it may be that an attempt to produce an embryo from human ESC-derived cells would be prohibited because of the huge and potentially tragic implications of bringing an abnormal child into the world. Nevertheless, this work is important scientifically and may lead to a better understanding of the earlier stages of gamete and embryo development without ever leading to a pregnancy. It may therefore be of significant clinical benefit without being so ethically challenging.
References Chen, H.F., Jan, P.S., Kuo, H.C., Wu, F.C., Lan, C.W., Huang, M.C., Chien, C.L., Ho, H.N., 2014. Granulosa cells and retinoic acid cotreatment enrich potential germ cells from manually selected Oct4EGP expressing human embryonic stem cells. Reprod. Biomed. Online 29 (in this issue). Hayashi, K., Ogushi, S., Kurimoto, K., Shimamoto, S., Ohta, H., Saitou, M., 2012. Offspring from oocytes derived from in-vitro primordial germ cell-like cells in mice. Science 338, 971–975. Lan, C.W., Chen, M.J., Jan, P.S., Chen, H.F., Ho, H.N., 2013. Differentiation of human embryonic stem cells into functional ovarian granulose-like cells. J. Clin. Endocrinol. Metab. 98, 3713–3723. Nayernia, K., Nolte, J., Michelmann, H.W., Rathsack, K., Drusenheimer, N., Dev, A., Wulf, G., Ehrmann, I.E., Elliott, D.J., Okpanyi, V., Zechner, U., Haaf, T., Meinhardt, A., Engel, W., 2006. In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev. Cell 11, 125– 132. West, F.D., Terlouw, S.L., Kwon, D.J., Mumaw, J.L., Dhara, S.K., Hasen, K., Dobrinsky, J.R., Stice, S.L., 2010. Porcine induced pluripotent stem cells produce chimeric offspring. Stem Cells Dev. 19, 1211–1220. Zhao, X.-Y., Li, W., Lv, Z., Liu, L., Tong, M., Hai, T., Hao, J., Guo, C.-L., Ma, Q.-W., Wang, L., Zeng, F., Zhou, Q., 2009. iPS cells produce viable mice through tetraploid complementation. Nature 461, 86–90.
http://dx.doi.org/10.1016/j.rbmo.2014.07.004 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Bill Ledger E-mail address: offi[email protected]
