Reversion of the differentiated phenotype and maturation block in Sertoli cells in pathological human testis

Abstract

To study the relationship between abnormal Sertoli cell differentiation and spermatogenic impairment, we examined the expression of Sertoli cell markers normally lost at puberty, cytokeratin 18 (CK18), anti-Müllerian hormone (AMH) and M2A antigen, in three children (aged 1-2 years), 50 adults (aged 19-45 years) with obstructive or non-obstructive azoospermia or oligozoospermia, and six patients (aged 1-18 years) with 5 alpha-reductase deficiency. There was CK18 and/or AMH expression, but never M2A antigen expression, associated with spermatogonial arrest or Sertoli cell-only (SCO) syndrome in infertile men. Loss of M2A antigen suggests the transition of Sertoli cells to an adult phenotype, while CK18 and/or AMH expression may be a manifestation of de-differentiation of Sertoli cells. In 5 alpha-reductase deficiency, there was a sequential loss of CK18, M2A antigen and AMH around puberty, associated with partial spermatogenesis. The persistence of immature Sertoli cells expressing M2A antigen was associated with prepubertal seminiferous cords and SCO syndrome. Therefore, 5 alpha-reductase deficiency may prevent the maturation of Sertoli cells, resulting in impairment of spermatogenesis, and loss of M2A antigen expression coincides with a critical step in the Sertoli cell maturation. High follicle stimulating hormone concentrations due to failure of normal Sertoli cell differentiation indicate a normal development pattern of the hypothalamic-pituitary-gonadal axis.

Transcriptome profiling of the developing postnatal mouse testis using next-generation sequencing

“…AMH causes the Müllerian duct to degenerate in XY embryos and promotes testicle differentiation. It has been reported that Amh and Krt18 are expressed in immature testes, but are absent in adult testes [13,67,68]. Unexpectedly, we detected both of them in adult male mice.…”

Cytokeratin 18 expression in immature Sertoli cells: co-localization with interstitial lymphocytic infiltrates.

“…21 of the 51 cases showed seminiferous tubules with Sertoli cells expressing cytokeratin 18. These tubules show close similarities with those indicated within former studies [5,6]. In accordance with these studies we additionally observed cytokeratin 18 expression in unfolded tubules with spermatogenic arrest at the level of spermatogonia or only few remaining Sertoli cells and partially sclerohyalinized tubular membranes.…”

“…One of these proteins is cytokeratin 18, an intermediate filament protein, which is consistently expressed in immature Sertoli cells of (normal) prepubertal seminiferous tubules, but is completely absent in normal, mature seminiferous tubules [1]. Cytokeratin 18 immunoactivity was found in Sertoli cells of tubules showing spermatogenic arrest at the level of spermatogonia and in some Sertoli cell only tubules with immature Sertoli cells which are frequently observed within so-called mixed atrophy biopsies [1][2][3][4][5][6][7]. Therefore, the immunohistochemical detection of cytokeratin 18 in Sertoli cells is supposed to be a sensitive marker for immature Sertoli cells.…”

Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood

“…In humans, cytokeratin 18 is a robust marker of immature Sertoli cells and in adult testes it has been used to identify seminiferous tubules in which the Sertoli cells have not matured (Stosiek et al, 1990;Steger et al, 1996Steger et al, , 1999Maymon et al, 2000), though this has also been indicated as reflecting de-differentiation of mature Sertoli cells (Kliesch et al, 1998;Steger et al, 1999).…”

“…M2A is expressed only by immature and not mature Sertoli cells in humans (Baumal et al, 1989), and its expression may persist in patients in whom disorders of spermatogenesis are present (Steger et al,1999;Blagosklonova et al, 2002).…”