Human embryonic stem cells (hESCs) recently celebrated the 10th anniversary of their discovery, and in the decade since their isolation they have possibly received more press coverage, both over their many potential applications as well as ethical concerns, than any other type of stem cell. In the last decade, much progress has been made in better understanding these cells and their capabilities. hESCs hold much promise not only for being cellular models of human development and function, but also for use in the field of regenerative medicine. However, due to ethical and application concerns, only recently have these cells made it to clinical trials.

Figure 1: The Blastocyst. Human embryonic stem cells are isolated from early-stage embryos in the late blastocyst stage, about four or five days after fertilization. The blastocyst is a hollow sphere made of approximately 150 cells and contains three distinct areas: the trophoblast, which is the surrounding outer layer that later becomes the placenta, the blastocoel, which is a fluid-filled cavity within the blastocyst, and the inner cell mass, also known as the embryoblast, which can become the embryo proper, or fetus, and is where hESCs are isolated from.

Though human embryonic stem cells were isolated just over a decade ago, embryonic stem cells were successfully isolated from other animals before this. Nearly 30 years ago, two groups independently reported the isolation of mouse embryonic stem cells (mESCs) (Martin, 1981; Evans and Kaufman, 1981). The mESCs were isolated from early-stage mouse embryos, approximately four to six days post-fertilization (out of 21 days total for mouse gestation). At this point in development, the embryo is in the late blastocyst stage (see figure 1). It was not until the mid-1990s that this feat was accomplished with non-human primates by Dr. James Thomsons group (Thomson et al., 1995). Only a few years later, embryonic stem cells isolated from humans, once again by Thomsons group, in 1998 (Thomson et al., 1998).

It is important to understand where hESCs come from in order to understand the ethical arguments that surround them, as well as their enormous, innate biological potential. Like mESCs, hESCs are isolated from early-stage embryos that are, specifically, in the late blastocyst stage, about four or five days after fertilization. After the fertilized egg cell starts cell division, what is referred to as the blastocyst occurs once the cell has divided into a hollow sphere made up of approximately 150 cells (see figure 1). At this point, the embryo has not even yet been implanted in the uterus. The blastocyst contains three distinct areas: the trophoblast, which is the surrounding outer layer that later becomes the placenta, the blastocoel, which is a fluid-filled cavity within the blastocyst, and the inner cell mass, also known as the embryoblast, which can become the embryo proper, or fetus. Embryonic stem cells can be created from cells taken from the inner cell mass (Stem Cell Basics: What are embryonic stem cells?, 2009). Because these cells are taken from such an early stage in development, they have the ability to become cells of any tissue type (except for the whole embryo itself), making them pluripotent. The pluripotency of hESCs is probably the trait that contributes most to their enormous potential, both as models of cell function and human development and, potentially, for uses in regenerative medicine. Being pluripotent and seemingly unlimited in supply separates hESCs from adult stem cells, which are multipotent or unipotent, able to become a more select group of cell types, and more limited in their cellular lifespan.

Because these cells are taken from human embryos, researchers have taken many steps to address ethical concerns. For the original creation of hESCs in 1998, blastocysts used were donated with full donor consent from in vitro fertilization (IVF) clinics (Thomson et al., 1998). Additionally, many researchers use blastocysts that would have been discarded by the IVF clinic because the embryos were damaged in some way and would never develop properly (Cowan et al., 2004; Suss-Toby et al., 2004; Jiang et al., 2008). Researchers have even found ways to isolate human embryonic stem cells while leaving the donor embryo intact and potentially able to develop normally; even earlier in development than the blastocyst stage, when the fertilized egg contains only 8 to 10 cells, researchers have shown that they can remove one of these cells and create a line of hESCs and the remaining cells will continue to function as usual (Klimanskaya et al., 2006). The National Academies has also developed extensive guidelines of ethical standards for researchers to follow.

Figure 2: A Human Embryonic Stem Cell Colony. Human embryonic stem cells grow in colonies, or groups of stem cells, along with supportive fibroblastic cells called feeder cells.

Though there have been many obstacles in place that have delayed hESCs from being widely used in regenerative medicine, much progress has been made in overcoming them. Because of their pluripotency, one defining feature of hESCs is the ability to create a tumor when injected into a mouse. These tumors, called teratomas, are tumors made up of a wide variety of different cell types. Consequently, it is important that all hESCs be completely differentiated into the desired target cell type for therapies, as undifferentiated hESCs could potentially create teratomas when used in humans (Thomson et al., 1998). Additionally, hESCs are often co-cultured with other supportive fibroblast cells, called feeder cells, and many such cells are of mouse origin (Thomson et al., 1998) (see figure 2). This raises concerns of non-human contaminants in hESC cultures, though it is an area of much study and many alternative methods that can create completely xeno-free culture systems have been espoused (Lannon et al., 2008). Lastly, there is difficulty in making patient-specific cells from hESCs, which is less of a problem for using many adult stem cells. However, this last problem, along with aforementioned ethical concerns, is quickly being addressed with the recent creation of hESC-like cells from adult cells, termed induced pluripotent stem cells (Yu et al., 2007; Takahashi et al., 2007).

Overall, hESCs have made much progress in the decade since their discovery, despite the hurdles set before them. Recently, many previous political restrictions have recently been removed by President Obama and researchers have even recently had FDA approval for the first clinical studies. These first clinical studies, specifically for using hESCs to treat spinal cord injuries, hopefully mark just the beginning for more clinical studies using these very promising stem cells.

References

Cowan, C. A., Klimanskaya, I., McMahon, J., Atienza, J., Witmyer, J., Zucker, J. P., Wang, S., Morton, C. C., McMahon, A. P., Powers, D., and Melton, D. A. Derivation of Embryonic Stem-Cell Lines from Human Blastocysts. New Engl. J. of Med. 2004. 350: 1353-1356. View Article

Evans, M. J. and Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981. 292: 154 156. View Article

Jiang, Y., Sun, X., Long, X., Du, H., Chen, X., Yin, Y., Huang, S., Wang, W., and Xiao, G. Derivation of two human embryonic stem cell lines form discarded blastocysts and maintained in conditioned media from human foreskin fibroblasts feeder cells without serum. Cell Research. 2008. 18:s42. View Article

Klimanskaya, I., Chung, Y., Becker, S., Lu, S., and Lanza, R. Human embryonic stem cell lines derived from single blastomeres. Nature. 2006. 444: 481-485. View Article

Lannon, C., Moody, J., King, D., Thomas, T., Eaves, A., and Miller, C. A defined, feeder-independent medium for human embryonic stem cell culture. Cell Research. 2008. 18:s34. View Article

Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. PNAS. 1981. 78(12): 7634-7638. View Article

Stem Cell Basics: What are embryonic stem cells? In Stem Cell Information [World Wide Web site]. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2009 [cited Friday, April 17, 2009]. Available at: http://stemcells.nih.gov/info/basics/basics3

Suss-Toby, E., Gerecht-Nir, S., Amit, M., Manor, D. and Itskovitz-Eldor, J. Derivation of a diploid human embryonic stem cell line from a mononuclear zygote. Human Reprod. 2004. 19(3): 670-675. View Article

Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell. 2007. 131(5): 861-672. View Article

Thomson, J. A., Kalishman, J., Golos, T. G., Durning, M., Harris, C. P., Becker, R. A., and J P Hearn. Isolation of a primate embryonic stem cell line. Proc. Natl. Acad. Sci. 1995. 92: 7844 7848. View Article

Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., and Jones, J. M. Science. Embryonic Stem Cell Lines Derived from Human Blastocysts. 1998. 282(5391): 1145 1147. View Article

Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, I. I., Thomson, J. A. Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science. 2007. 318(5858): 1917 1920. View Article

Original The Blastocyst image modified from the Wikimedia Commons and image of a Human Embryonic Stem Cell Colony also taken from the Wikimedia Commons. Both are redistributed freely as they are in the public domain.

admin Embryonic Stem Cells clinical trials, embryonic, history, news, regenerative medicine 2009-2010, Teisha Rowland. All rights reserved.

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