Regulation of Spermatogonial Stem Cell Self-Renewal in Mammals

Abstract

Mammalian spermatogenesis is a classic adult stem cell-dependent process, supported by selfrenewal and differentiation of spermatogonial stem cells (SSCs). Studying SSCs provides a model to better understand adult stem cell biology, and deciphering the mechanisms that control SSC functions may lead to treatment of male infertility and an understanding of the etiology of testicular germ cell tumor formation. Self-renewal of rodent SSCs is greatly influenced by the niche factor glial cell line-derived neurotrophic factor (GDNF). In mouse SSCs, GDNF activation upregulates expression of the transcription factor-encoding genes bcl6b, etv5, and lhx1, which influence SSC self-renewal. Additionally, the non-GDNF-stimulated transcription factors Plzf and Taf4b have been implicated in regulating SSC functions. Together, these molecules are part of a robust gene network controlling SSC fate decisions that may parallel the regulatory networks in other adult stem cell populations.

Multipotent male germline stem cells (mGSCs) from neonate porcine testis

“…It was reported that after in vitro cultures of mammalian mGSCs shared similar phenotypical characteristics as SSCs and pluripotent ES cells (Oatley and Brinster 2008;SuYoung et al 2009;Hua et al 2011). Pluripotency related markers of NANOG, Oct-4, and SSC markers: promyelocytic leukemia zinc-finger (PLZF), GFRA1, ITGA6 (α6-integrin, CD49f), and THY1 were expressed at higher levels (Kanatsu-Shinohara et al 2008;Kuijk et al 2009;Zheng et al 2013).…”

“…Derivation of pluripotent cells from male germ cells is enhanced by the cytokines, such as epidermal growth factor (EGF), Colony stimulating factor 1 (CSF1), Leukemia inhibitory factor (LIF), Glial cell-derived neurotrophic factor (GDNF) (Kuijk et al 2009;Zhu et al 2012). GDNF is secreted by the somatic Sertoli cells and peritubular cells, and is a well-known inducer of mouse SSC proliferation in vitro (Oatley et al 2008). Binding of GDNF to the GDNF-family receptor α1 (GFRα1) catalyses the activation of the c-RET receptor, which activates several signal cascades, such as PI3K/AKT, MEK and SCR kinases (Zheng et al 2013).…”

“…Binding of GDNF to the GDNF-family receptor α1 (GFRα1) catalyses the activation of the c-RET receptor, which activates several signal cascades, such as PI3K/AKT, MEK and SCR kinases (Zheng et al 2013). GDNF activation upregulates expression of the transcription factor-encoding genes Bcl6b, Etv5, and Lhx1, which influence mouse SSC selfrenewal (Oatley and Brinster 2008). EGF and FGF had a positive effect on the number and size of the SSC-like colonies in primary cultures of neonate pig testis.…”

Epigenetic modifications and self-renewal regulation of mouse germline stem cells

“…Although activated Akt-GS cells could proliferate in the absence of GDNF, activation of Akt alone was not sufficient to drive SSC self-renewal; the cells also required co-stimulation with bFGF because epidermal growth factor (EGF) could not replace bFGF [44]. Despite the increasing number of identified genes involved in SSC self-renewal [40][41][42]46], how the exogenous cytokine signals are converted to drive the SSC self-renewal machinery remains unclear.…”

Pluripotency of Male Germline Stem Cells

“…Only the A single (A s ) population is believed to have stem cell activity. The other spermatogonial populations, which are generated from the mitotic division of type A s cells, are assumed to be irreversibly differentiated and committed to sperm production (Oatley and Brinster, 2008). Notably, Nakagamwa et al (2010) showed that the cellular states of A s -A al (A aligned ) spermatogonia cells in the testes can undergo reversible inter-conversion, even though they are heterogeneous in terms of glial cell line-derived neurotrophic factor (GDNF) family receptor alpha-1 (GFRα1)/neurogenin 3 (Ngn3) expression.…”