From stem cells to spermatozoa and back

Abstract

As a strategy for survival, the metazoa segregated immortal germ cells from the mortal soma by an early differentiation process and thereby reproduced asymmetrically in a specialised tissue. The legacy of this process is seen in the generation of mammalian gametes which are derived from a founder population of primordial germ cells (PGCs) that are determined early in embryogenesis and set aside for unique development. Understanding the mechanisms of PGC determination and differentiation is important for elucidating causes of infertility and how endocrine disrupting chemicals may increase susceptibility to congenital reproductive abnormalities and conditions such as testicular cancer in adulthood (testicular dysgenesis syndrome). Primordial germ cells are closely related to embryonic stem (ESCs) cells and embryonic germ (EG) cells and comparisons between these various cell types are providing new information about pluripotency and epigenetic processes. Murine embryonic stem cells can differentiate to PGCs, gametes and even blastocysts. Recently live mouse pups were born from sperm generated from ESCs. Although investigations are still preliminary, human embryonic stem cells (hESCs) apparently display a similar developmental capacity to generate PGCs and subsequently gametes. The findings indicate hESCs have the potential to differentiate to PGCs (as determined with surface markers and gene expression profiles) although these phenotypes represented a small proportion of the total cell population (approximately 0.1%). Postmeiotic spermatids have been identified using specific markers, while primordial follicular structures have been observed in culture although not characterised definitely. Germ cells will enter meiosis autonomously and develop as oocytes unless meiosis is blocked and cells are induced into a spermatogenic pathway. During hESC differentiation both pathways seem to occur, regardless of the sex karyotype. Exactly how gamete-like cells are generated during stem cell culture remains unclear especially as conditions are currently ill defined. The findings are discussed in relation to the mechanisms of human PGC and gamete development and the biotechnology of hESCs and hEG cells.