Updates in Sertoli Cell-Mediated Signaling During Spermatogenesis and Advances in Restoring Sertoli Cell Function

Abstract

Since their initial description by Enrico Sertoli in 1865, Sertoli cells have continued to enchant testis biologists. Testis size and germ cell carrying capacity are intimately tied to Sertoli cell number and function. One critical Sertoli cell function is signaling from Sertoli cells to germ cells as part of regulation of the spermatogenic cycle. Sertoli cell signals can be endocrine or paracrine in nature. Here we review recent advances in understanding the interplay of Sertoli cell endocrine and paracrine signals that regulate germ cell state. Although these findings have long-term implications for treating male infertility, recent breakthroughs in Sertoli cell transplantation have more immediate implications. We summarize the surge of advances in Sertoli cell ablation and transplantation, both of which are wedded to a growing understanding of the unique Sertoli cell niche in the transitional zone of the testis.

Keywords: AR signaling; Exosome extracellular vesicle (EV); FSH signaling; Sertoli cell ablation; Sertoli cell transplantation; Spermatogenesis; sertoli cell (SC) niche; transitional zone (TZ).

Figure 1

Architecture of Sertoli cells in the adult mouse seminiferous tubule. The bodies of Sertoli cell cytoplasm (green) can be seen engulfing germ cells (red) from basal lamina to lumen while Sertoli cell nuclei (blue) are located basally. Top row: zoomed inset from grey boxed region in Middle Row: seminiferous tubule cross section at stage V-VI. Bottom Row: Longitudinal sections showing multiple stages. All scale bars are 50µm.

Figure 2

Seminiferous epithelial stages of mouse and human spermatogenesis as classic spermatogenesis cycle staging charts using germ cell associations and morphology. Spermatogenesis is the process of sperm development and involves phases of mitosis, meiosis, and spermiogenesis (morphological cell changes). (A) Spermatogenesis in mice is a cycle that takes ~8.6 days (–14). The time necessary for a germ cell to go from type A spermatogonia to spermatozoa (the complete process or duration of spermatogenesis) is about 35 days (12, 13, 15). In mice, spermatogenesis is divided into 12 stages (I-XII) and 16 spermatid developmental steps. A, In, and B are type A, intermediate, and type B spermatogonia, respectively. Pl, L, Z, P, D, M, and 2º are preleptotene, leptotene, zygotene, pachytene, diplotene, meiotic, and secondary spermatocytes, respectively. Steps of spermatid development are numbered 1-16. Sections were stained with Periodic Acid Schiff’s regent-hematoxylin (PAS-H), which is a conventional staining for staging of mouse testis sections. Scale is 20μm. (B). Spermatogenesis in men is a 16 day cycle with a complete duration that was classically determined to be 64 days but modern methods show to be closer to 74 days (–21). In humans, spermatogenesis is divided into 6 stages (I-VI) and 6 spermatid developmental steps. Adark, Apale and B are type A dark, type A pale and type B spermatogonia, respectively. Pl, L, Z, P, D, M, A and 2º are preleptotene, leptotene, zygotene, pachytene, diplotene, meiotic metaphase, meiotic anaphase and secondary spermatocytes, respectively. Steps of spermatid development are labeled Sa, Sb1, Sb2, Sc, Sd1 and Sd2. Sections were stained with Periodic Acid Schiff’s regent-hematoxylin (PAS-H), which is a conventional staining for human testis histology assessment. Scale is 20μm.