Reduced serum testosterone (T), or hypogonadism, affects millions of men and is associated with many pathologies, including infertility, cardiovascular diseases, metabolic syndrome, and decreased libido and sexual function. Administering T-replacement therapy (TRT) reverses many of the symptoms associated with low T levels. However, TRT is linked to side effects such as infertility and increased risk of prostate cancer and cardiovascular diseases. Thus, there is a need to obtain T-producing cells that could be used to treat hypogonadism via transplantation and reestablishment of T producing cell lineages in the body. T is synthesized by Leydig cells (LCs), proposed to derive from mesenchymal cells of mesonephric origin. Although mesenchymal cells have been successfully induced into LCs, the limited source and possible trauma to donors hinders their application to clinical therapies. Alternatively, human induced pluripotent stem cells (hiPSCs), which are expandable in culture and have the potential to differentiate into all somatic cell types, have become the emerging source of autologous cell therapies. We have successfully induced the differentiation of hiPSCs into either human Leydig-like (hLLCs) or adrenal-like cells (hALCs) using chemically defined culture conditions. Factors critical for the development of LCs were added to both culture systems. hLLCs expressed all steroidogenic genes and proteins important for T biosynthesis, synthesized T rather than cortisol, secreted steroid hormones in response to dibutyryl-cAMP and 22(R)-hydroxycholesterol, and displayed ultrastructural features resembling LCs. By contrast, hALCs synthesized cortisol rather than T. The success in generating hiPSC derived hLLCs with broad human LC (hLC) features supports the potential for hiPSC-based hLC regeneration.
Significance
Our results suggest that both androgen- and cortisol-producing human Leydig and adrenal cells can be induced from human induced pluripotent stem cells. This bidirectional approach offers insights into the events specifying different steroidogenic cell populations sharing developmental origins. More importantly, our study provides a way to generate possible transplantation materials for clinical therapies. Human Leydig-like cells could also be useful for in vitro studies of testicular development and pathologies of testis-relevant diseases, and for the discovery of new drugs inducing androgen formation for hypogonadism treatment.
In sum, our study describes an experimental approach with the potential of providing transplantation material for clinical therapy. Moreover, hiPSC-derived LCs can potentially be used for in vitro studies of testicular development and pathologies of testis relevant diseases and the discovery of new drugs that induce androgen formation and thus could treat hypogonadism (59).
