Stem Cells in Reproductive Medicine

Joseph Itskovitz-Eldor, M.D., D.Sc.

There have been few areas in the history of science and medicine that have generated such overwhelming interest within both the scientific community and the general public as has research on stem cells. The focus, it seems, lies in human embryonic stem cells (ESCs), primarily due to the remarkable potential of these pluripotent cells, but also because of the ethical issues surrounding the use and destruction of human blastocysts required for their derivation.

Albeit the above, it is worth noting that the concept of ‘stem cells’ originates in the mechanism of tissue renewal and homeostasis of the hematopoietic system in the adult.[1] Stem cell therapy was applied fully for the first time when hematopoietic stem cells of the bone marrow or cord blood were transplanted into the adult; indeed, in the near future it is adult stem cells that will pave the way into clinical cell therapy applications of stem cells rather than their embryonic counterparts.

In our area of expertise-reproductive medicine in prima vista clinical applications of stem cells-it seems to still be a thing of the distant future, but a learned close look reveals that only a handful of disciplines are as close and as relevant as reproductive biology and medicine are to the research on stem cells, especially those stem cells derived from the fetus or the embryo. Since Edwards' attempt to derive stem cells from rabbit blastocysts,[2] or Bongso's attempt to do the same from the human,[3] reproductive biology and medicine in general-and assisted reproductive technologies in particular-have played a crucial and central role in stem cell biology, to the extent that their involvement led, amongst other achievements, to the derivation of mouse ES cells,[4] [5] and ES cells and embryonic germ cells in the human.[6] [7] It is clear that should therapeutic cloning for the derivation of genetically matched human ESCs become practical, it will enjoy great strides thanks to the clinicians and scientists involved in assisted reproductive technologies.

Reproductive medicine also clearly touches on basic and translational research related to fetal and adult stem cells. Fetal stem cell therapies-for the correction of genetic defects in utero or transplantation of testicular stem cells for the preservation of fertility-are some of the topics that come in direct contact with our area of specialty.

This issue of Seminars commences with the article, “Prospectives of stem cell research,” by Drs. Gokhale and Andrews. The authors address the stem cell concept proposed by Osgood some 50 years ago-an “immature” cell type in multicellular organisms that may give rise to a more differentiated daughter cell and a copy of the parent cell.[1] [8] They remind us that isolation of both mouse and primate ESCs from the inner cell mass (ICM) of blastocyst-stage embryos were preceded by studies of self-renewing embryonal carcinoma (EC) cells.[9] The accumulating experience in ESC research enabled Evans and Kaufman,[4] and Martin[5] to produce the first ESCs from the ICM of a mouse, and later on of a human.[6] The progress made in our understanding of the stem cell state, the cells' self-renewal, and adaptation to culture are also discussed.

Other possible sources and practical aspects of the derivation and growth of human ESCs are presented by Drs. Amit and Itskovitz-Eldor in their article on “Sources and derivation of human ESCs.” Newly developed methods for growing the cells in controlled and well-defined conditions that are animal product-free, serum-free, and feeder-free make possible the use of these cells for future medical and industrial purposes.

Similar to ESCs, embryonic germ cells (EGCs) are pluripotent cells with unlimited self-renewal ability, which can give rise to derivatives of all three germ layers. In the human, these cells were derived by Chamblott et al[7] from primordial germ cells located in the gonadal ridges and mesenteries of 5- to 9-week postfertilization human embryos. In contrast to human ESCs, our knowledge of EGCs is fairly limited. In their article “Embryonic germ cells,” Drs. Kerr, Gearhart, Elliott, and Donovan discuss the differences between ESCs and EGCs, the ways to derive and grow them, and the potential use of EGCs in cell therapy.

The study of early human development from its very first days following implantation in the womb is extremely restricted because of pragmatic and ethical reasons. In this respect, human ESCs may serve as a unique model in studying the basic aspects of this period. One of the critical developmental stages is the differentiation into the trophoblast lineage and the formation of the placenta. In their article, “Human embryonic stem cells as a model for trophoblast differentiation,” Drs. Golos, Pollastrini, and Gerami-Naini describe the ability of human ESCs to differentiate into the trophoblast lineage in various differentiation models, including a 3D approach.[10] With the expanding availability of these models, it will be possible to gain insight into the infertility, early pregnancy loss, teralogenicity, and many other aspects related to maternal and fetal health.

Several reports have recently described the ability of human and mouse ESCs to differentiate into primordial germs cells (PGCs)-the precursors of gametes. Some early results suggest that ESC-derived PGCs can spontaneously differentiate into gametes. In their article, “Embryonic stem cells as a potential source of gametes,” Drs. Ko and Schöler summarize the information we have so far in regard to this exciting field, and describe the long and winding road still ahead of us in obtaining functional gametes from ESCs. The handiness of gametes, let alone oocytes, is unimaginably important for research, and possibly also for medical use.[11]

As previously mentioned, several significant limitations hinder the study of early human development. The availability of gametes, pre-implantation embryos, and ESCs allow the performance of important research that could advance the task of global gene expression profiling during the first days of human development.[12] Drs. Aiba, Carter, Matoba, and Ko depict the systemic approaches for developmental genomics or embryogenomics. In their article, “Genomic approach to early embryogenesis and stem cell biology,” the authors survey the different methods and the biological significance of global gene expression profiling and describe the transition to genomic scale functional studies of genes involved in early events of human development.

In comparison to embryonic and adult stem cells, fetal stem cells may be considered an intermediate cell type in terms of their plasticity, their proliferative capacity, and the ethical concerns associated with stem cell research. They can be derived from most tissues throughout the fetus life cycle, including the placenta, the umbilical cord, the amniotic fluid, the bone marrow, and the liver.[13] A better understanding of fetal stem cells will help gain further insights into the differentiation processes and organogenesis of the embryo. The article, “Fetal stem cells: betwixt and between,” by Drs. Guillot, O'Donoghue, Kurata, and Fisk discusses the apparent advantages these cells have over adult stem cells, provides up-to-date sources for harvesting them, and lists possible clinical applications. In utero stem cell transplantation, for one, exploits the ontogeny of the immune system to facilitate allogenomic stem cell engraftment to correct genetic defects.[14] Dr. Westgren, in his article, “In utero stem cell transplantation,” reviews the current experimental and clinical progress made in this field, which is, unfortunately, quite limited. Progress made in molecular-based prenatal screening and stem cell biology will hopefully help exhaust the potential of this therapeutic approach.

The benefit of transplantation of cord blood for reconstitution of bone marrow is well established, as is the need to preserve cord blood in public banks. However, perinatologists are often asked about the need and the applicability of commercially directed cord stem cell cryopreservation, a question that cannot be answered explicitly at the present time. Several studies indicate that cord stem cells enjoy a greater potential than that known by the treatment of blood diseases. Dr. Sanchez-Ramos focuses his survey, “Stem cells from umbilical cord blood,” on the plasticity of various stem cells of the cord blood and their prospective use apart from treating blood illnesses, such as repair of traumatic and degenerative diseases of the nervous system.[15]

Two articles in this issue deal with adult stem cells. The first presents testicular stem cells that give rise to spermatogenic cells and thus transmit parental genetic information to the offspring. Drs. Goossens and Tournaye, in their article, “Testicular stem cells,” examine the basic aspects of testicular stem cell biology, as well as practical approaches for their culture and cryopreservation for fertility preservation in pre-pubertal patients treated for cancer.[16]

Lastly, Drs. Serafini and Verfaillie, in their article, “Adult stem cells pluripotency: state of the art,” review the published reports that point to the intriguing possibility of the existence of pluripotent adult stem cells that can unexpectedly differentiate into cell types of all three germ layers akin to the process ESCs undergo.[17] This opposes the common perception that adult stem cells can only differentiate into a spectrum of cells consistent with their tissue of origin.

The aim of this Seminars issue was to bring together the knowledge, experience, and vision of diversified authoritative figures in the area of stem cells as they apply to reproductive medicine. The distinguished authors of this issue made a great effort to provide the readers with the most up-to-date information, and their fruitful dedication and undertaking are most appreciated. I hope that this special issue on stem cells raises the awareness of the great promise waiting to unfold via basic and translational research, and that the data presented here increase the involvement of reproductive medicine in this exciting and revolutionizing field.

REFERENCES

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