Roles of Spermatogonial Stem Cells in Spermatogenesis and Fertility Restoration

Abstract

Spermatogonial stem cells (SSCs) are a group of adult stem cells in the testis that serve as the foundation of continuous spermatogenesis and male fertility. SSCs are capable of self-renewal to maintain the stability of the stem cell pool and differentiation to produce mature spermatozoa. Dysfunction of SSCs leads to male infertility. Therefore, dissection of the regulatory network of SSCs is of great significance in understanding the fundamental molecular mechanisms of spermatogonial stem cell function in spermatogenesis and the pathogenesis of male infertility. Furthermore, a better understanding of SSC biology will allow us to culture and differentiate SSCs in vitro, which may provide novel stem cell-based therapy for assisted reproduction. This review summarizes the latest research progress on the regulation of SSCs, and the potential application of SSCs for fertility restoration through in vivo and in vitro spermatogenesis. We anticipate that the knowledge gained will advance the application of SSCs to improve male fertility. Furthermore, in vitro spermatogenesis from SSCs sets the stage for the production of SSCs from induced pluripotent stem cells (iPSCs) and subsequent spermatogenesis.

Keywords: 3D culture; in vitro; in vivo; male infertility; spermatogenesis; spermatogonia; stem cell.

Figure 1

Schematic diagram of the niche of SSCs and the regulatory factors involved in maintaining the stemness and self-renewal of SSCs. Undifferentiated SSCs are localized at the basement membrane. Germ cells maintain the close contact with the Sertoli cells inside the seminiferous epithelium. Peritubular myoid cells surround the seminiferous tubules to form testicular cords. The interstitial compartment consists of many somatic cell types including Leydig cells, mesenchymal cells and immune cells. Bioactive factors in the niche play crucial role in self-renewal and differentiation of SSCs. CXCL12/CXCR4, FGFs, and VEGFA act in synergy with GDNF to maintain SSCs. Retinoic acid (RA) induces the differentiation of SSCs by downregulation, at least in part, of GDNF expression and activation of SCF and BMP4. Transcription factors, PLZF and FOXO1, are involved in regulating SSCs maintenance and spermatogenesis by acting on a subset of downstream target gene. MicroRNAs, including miR-1908-3p, miR-112-5p and miR-31-5p, also act as critical regulators in spermatogenesis.

Figure 2

Schematic diagram of SSC-based fertility restoration in humans. A sample of testicular tissue of prepubertal boys, who receive gonadotoxic treatment, is retrieved and cryopreserved. Spermatogenesis may be induced after treatment either in vivo or in vitro.