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Vincent Center for Reproductive Biology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Jose M. Teixeira, Massachusetts General Hospital, Vincent Center for Reproductive Biology, Thier 913, 55 Fruit Street, Boston, Massachusetts. E-mail: teixeira{at}helix.mgh.harvard.edu.
Embryonic stem (ES) cells, pluripotent cells derived from the inner cell mass of d-5 blastocysts, have the potential to dramatically alter the therapeutic outlook of patients suffering from chronic, debilitating, and degenerative disorders such as diabetes, Parkinson’s, and various myopathies. For example, the differentiation of spontaneously beating cardiomyocytes derived from human ES cells that have formed embryoid bodies (EBs) in vitro could be used in stem cell therapies for patients with myocardial infarction or cardiomyopathies (1, 2, 3). In mice, ES cells can give rise to every cell type in the body when injected back into the blastocyst, suggesting that the therapeutic cell replacement potential for these cells is now limited only by our imagination. Indeed, it is the ability of genetically altered ES cells to contribute to the germ line that has allowed for the generation of knockout mice with their resultant phenotypes, radically altering the way we study the function of any given protein. Although there are very few cases reported where ES cell transplants have been shown to improve any pathological condition in any species (4, 5, 6, 7, 8), the excitement felt by researchers in the field of ES cell biology cannot be overstated. ES cell biology is still very much in its infancy; thus, the cocktail of factors, some of which are endocrine, such as androgens, needed for cell-specific differentiation are currently one of the major areas of investigation.
The requirement for androgens in reproductive tract differentiation during fetal, neonatal, and postnatal development is clear, as is the role of androgens in extragonadal settings such as skeletal muscle. However, the evidence for a putative role for androgens in early embryonic development is less compelling. For example, although Silva and Knight (9) showed that in vitro androgens and flutamide could significantly affect the rate of bovine zygotic cleavage, there was no observable effect on blastocyst formation or hatching. In contrast, in vivo flutamide treatment of pregnant rats significantly decreased embryo degeneration compared with controls (10). Experiments by Chang et al. (11) with murine ES cells, which are more amenable to experimentation, showed that they expressed the androgen receptor and responded to both androgens and nilutamide, a nonsteroidal antiandrogen. Significantly, this group showed relatively high levels of androgen receptor in the inner cell mass by quantitative RT-PCR compared with the levels found in blastocysts. However, no significant effect on the proliferation or the expression of a few chosen genes was observed with androgen treatment of ES cells; thus, the physiological implications of these studies remained to be elucidated.
In this issue of Endocrinology, the paper by Goldman-Johnson et al. (12) provides some tantalizing clues of a possible role for androgens in mouse ES cell differentiation, specifically cardiomyocyte differentiation. They show that addition of increasingly high concentrations of androgens to their normal ES cell differentiation protocol resulted in greater numbers of EBs with beating cells, which were assumed to be cardiomyocytes. Confirmation that there were more muscle cells in the androgen-treated group was provided by flow cytometry using tropomyosin and 
-actinin markers. Reassuringly, this was observed in both XY and XO ES cells. Additionally, fewer EBs with beating cells were observed if treated with flutamide, an androgen antagonist, and if an equivalent amount of flutamide was added along with testosterone, there was no observed enhancement in the number of beating EBs. Perhaps most startling of all was their observation that male ES cells not only express key enzymes necessary for androgen synthesis by RT-PCR but that they also synthesize testosterone at levels comparable to that observed with unstimulated Leydig cells in vitro, suggesting an autocrine mechanism for androgen-supported cardiomyocyte differentiation.
The physiological significance of these observations might not have been appreciated given the apparently normal cardiac development in androgen receptor mutant mice or the lack any reported cardiac deficiencies in testicular feminization of patients. However, there is evidence that testosterone might be a protective factor in myocardial ischemia (13) and that it may play an important role in cardiac growth and remodeling (14). One also has to wonder whether these observations are species or cell line specific. Skottman et al. (15) showed that human ES cells possessed specific subsets of differentially expressed genes, which suggests that genetic variation or differences in developmental potential might affect the proportion of EBs that differentiate into each germ layer. However, if ES cell therapies are ever to come to fruition for myocardial pathologies, then studies like those described by Goldman-Johnson et al. (12) will be increasingly necessary to understand ES cell biology with the ultimate goal of optimizing cell-specific differentiation protocols.
Murine ES cells have been used for some time to study a variety of endocrine systems, particularly to generate knockout mouse in vivo model systems. However, the endocrine potential of ES cells themselves has not been widely studied. This is in stark contrast to primary and tumor cells derived from endocrine organs, which have been invaluable in vitro model systems to study every aspect of endocrinology. Perhaps this has been due to the restrictive focus of endocrinology, whose textbook definition is the "action of hormones and the organs that produce them" or are affected by them (16). In addition to their largely unrealized potential to contribute differentiated cells to endocrine organs, ES cells, although not derived from any organ, have now been shown to produce and respond to a wide variety of factors including steroid hormones, which is well discussed in Goldman-Johnson et al. (12), a compelling beginning for this relatively new field of endocrinology, namely ES cell endocrinology.
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Abbreviations: EB, Embryoid body; ES, embryonic stem.
Received October 16, 2007.
Accepted for publication October 18, 2007.
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