Can we grow sperm? A translational perspective on the current animal and human spermatogenesis models

Abstract

There have been tremendous advances in both the diagnosis and treatment of male factor infertility; however, the mechanisms responsible to recreate spermatogenesis outside of the testicular environment continue to elude andrologists. Having the ability to 'grow' human sperm would be a tremendous advance in reproductive biology with multiple possible clinical applications, such as a treatment option for men with testicular failure and azoospermia of multiple etiologies. To understand the complexities of human spermatogenesis in a research environment, model systems have been designed with the intent to replicate the testicular microenvironment. Currently, there are both in vivo and in vitro model systems. In vivo model systems involve the transplantation of either spermatogonial stem cells or testicular xenographs. In vitro model systems involve the use of pluripotent stem cells and complex coculturing and/or three-dimensional culturing techniques. This review discusses the basic methodologies, possible clinical applications, benefits and limitations of each model system. Although these model systems have greatly improved our understanding of human spermatogenesis, we unfortunately have not been successful in demonstrating complete human spermatogenesis outside of the testicle. Asian Journal of Andrology (2011) 13, 677-682; doi:10.1038/aja.2011.88; published online 18 July 2011 Keywords: fertility preservation; spermatogenesis models; spermatogonial stem cells INTRODUCTIONRecreating human spermatogenesis outside of its original environment remains the 'Holy Grail' for generations of andrologists. To grow sperm is not only a matter of scientific curiosity, but also a quest for the treatment of male infertility. A well-characterized model for spermatogenesis in humans will have a huge impact on our understanding on the physiological and genetic pathways of male reproduction. Its clinical applications also extend to the study of human reproductive toxicology and preservation of fertility in treated cancer patients.While significant progress has been made in the laboratory, multiple obstacles remain. Current knowledge on the control of gonadogenesis, spermatogenesis and steroidogenesis are based on the examination of histology, immunohistochemistry, hormonal assays, and phenotypes of single gene or small groups of gene alterations in animal models. Human studies in male reproduction are hindered by the lack of human testicular specimens, which are not as readily available as our animal counterparts, for ethical and practical reasons. In this review, we will examine the existing literature on the experimental models and their limitations in growing sperm to provide a foundation for future investigation and clinical application ( Table 1).

Future Perspectives in the Diagnosis and Management of Unexplained Male Infertility

“…One such barrier is that the number of SSC that can be harvested from prepubertal testis is low and be insufficient to restore fertility upon transplantation [2]. The work by Sadri-Ardekani et al has demonstrated the ability to culture and propagate human postpubertal SSCs, allowing for the opportunity to expand an SSC population before transplantation [10].…”

“…Each cell type plays a role in maintaining and regulating stem cells. Sertoli cells form the blood-testis barrier and secrete numerous factors such as growth factors, steroids, androgen binding protein, and extracellular matrix components that help to regulate spermatogenesis [2]. Leydig cells, following stimulation by luteinizing hormone, produce androgens that are necessary for the regulation of spermatogenesis and the development of secondary sexual characteristics.…”

“…Just like human ES cells, human induced pluripotent stem cells (iPSCs) have been used to produce not only PGCs, but haploid-like cells as well [37]. While iPSCs may provide a means to continue advancement while avoiding controversy, iPSC production may be associated with genetic instability [2]. High-resolution single-nucleotide polymorphism (SNP) analysis was performed on pluripotent samples and an increased frequency of copy number variations and mutations [38].…”

“…Further refinement of this model could also lead to its use for human reproductive toxicology studies. Rather than use healthy subjects, the xenograft model can be used to determine the reproductive impact of various chemicals and pharmacologic agents [2].…”

Connecting cis-elements and trans-factors with mechanisms of developmental regulation of mRNA translation in meiotic and haploid mammalian spermatogenic cells

“…Many types of culture systems have been explored to identify genes and endocrine and paracrine factors that support spermatogenesis and to generate spermatozoa to produce genetically modified animals and remedy male infertility (reviewed in Lo & Domes (2011) and Hunter et al (2012)). It should be noted that culture systems that support abnormal development or yield small numbers of spermatozoa are adequate for many purposes.…”