Mechanistic Insights into the Regulation of the Spermatogonial Stem Cell Niche

Abstract

Potential therapeutic use of stem cells in the treatment of human diseases depends on our ability to control the balance of their differentiation and self-renewal in vitro and in vivo. The stem cell "niche," or specialized microenvironment, is now recognized as one of the major contributors to this regulation in many species. Our recent study, which was reported in Nature, was the first to demonstrate that expression of a vertebrate animal transcription factor is essential for the maintenance of a stem cell niche. In that letter, targeted disruption of ERM (Ets-related molecule), which was localized only in the somatic support cell of the testis, the Sertoli cell, resulted in failure of self-renewal by spermatogonial stem cells, following the first wave of spermatogenesis. One of the more important conclusions drawn was the realization that regulation of the stem cell niche during the perinatal period, a phase characterized by rapid mitosis of both spermatogonial stem cells and Sertoli cells, differed from that in the adult. It appears that the ERM-regulated pathways are coincident with the termination of Sertoli cell proliferation and commencement of the cycle of spermatogenesis, which is sustained by the same cell that regulates the stem cell niche. Several likely targets for ERM regulation are discussed, as well as their potential implications for increasing our understanding of spermatogonial stem cell activity and the uniqueness of the Sertoli cell's immune privilege and possible utility for the protection of transplanted adult stem cells.

Vascular endothelial growth factor regulates germ cell survival during establishment of spermatogenesis in the bovine testis

“…While we have cultured and grafted bovine testis tissue successfully, no researchers have treated tissue in vitro prior to grafting to determine whether the treatment modifies the germ cell population such that long-term sperm production is affected. Our testis tissue culture-grafting approach is a novel method to investigate factors important for germ cell biology because 1) sperm production in testis tissue grafts is a direct means to determine whether a specific treatment manipulates the germ cell population and 2) the specialized microenvironments (Honaramooz et al 2002, McLean 2005, Hess et al 2006, Yoshida et al 2007) established between germ and Sertoli cells are maintained.…”

Role of microRNAs in mammalian spermatogenesis and testicular germ cell tumors

“…The expression profile of miRNAs in testes is given in Table 1. miRNA and spermatogonial stem cell renewal Within the testis, the SSCs reside in a unique microenvironment, or 'niche', which includes the surrounding somatic cells. Spermatogenesis originates from SSCs, which have the dual property of continually renewing and undergoing differentiation into a spermatogonial progenitor that expands and further differentiates (Hess et al 2006, Ventela et al 2012, Dovere et al 2013, Silvan et al 2013, van den Driesche et al 2014, Guo et al 2014. In the rodent testis, SSCs are among undifferentiated spermatogonia that include Asingle (As), Apaired (Apr), and Aaligned (Aal) spermatogonia (Dym 1994).…”

Mouse models of testicular germ cell tumors

“…Germ cells undergo either a proliferative period (to maintain the progenitor population throughout the reproductive life of males) or meiosis (to mature germ cells) (Nagano et al, 2000). During these postnatal days, pre-Sertoli cells transform into mature Sertoli cells that support germ cell differentiation and spermatogenesis (Griswold, 1995;Hess et al, 2006). Remarkably, a significant proportion of PGCs remains scattered along the migratory route.…”