Development and Disease-Dependent Dynamics of Spermatogonial Subpopulations in Human Testicular Tissues

Abstract

Cancer therapy and conditioning treatments of non-malignant diseases affect spermatogonial function and may lead to male infertility. Data on the molecular properties of spermatogonia and the influence of disease and/or treatment on spermatogonial subpopulations remain limited. Here, we assessed if the density and percentage of spermatogonial subpopulation changes during development (n = 13) and due to disease and/or treatment (n = 18) in tissues stored in fertility preservation programs, using markers for spermatogonia (MAGEA4), undifferentiated spermatogonia (UTF1), proliferation (PCNA), and global DNA methylation (5mC). Throughout normal prepubertal testicular development, only the density of 5mC-positive spermatogonia significantly increased with age. In comparison, patients affected by disease and/or treatment showed a reduced density of UTF1-, PCNA- and 5mC-positive spermatogonia, whereas the percentage of spermatogonial subpopulations remained unchanged. As an exception, sickle cell disease patients treated with hydroxyurea displayed a reduction in both density and percentage of 5mC- positive spermatogonia. Our results demonstrate that, in general, a reduction in spermatogonial density does not alter the percentages of undifferentiated and proliferating spermatogonia, nor the establishment of global methylation. However, in sickle cell disease patients’, establishment of spermatogonial DNA methylation is impaired, which may be of importance for the potential use of this tissues in fertility preservation programs.

Hydroxyurea does not affect the spermatogonial pool in prepubertal patients with sickle cell disease

“…Of note, a research team recently reported a nonaffected spermatogonial pool in 3 SCD patients. 19 Other than the very small sample size, this contradictory result could be explained by the fact that the patients were compared with nontreated cancer patients, who may have low spermatogonial counts, unlike healthy boys. SCD is a hemoglobinopathy that affects patients from very early infancy as a result of chronic hemolytic anemia, multiple vasoocclusive complications, and painful crises.…”

“…The establishment of spermatogonial DNA methylation has been shown to be altered in prepubertal patients with SCD. 19 This could be another explanation for the spermatogonial depletion, as correct establishment of the methylation profile is necessary for spermatogonial maintenance. SCD treatments, such as transfusion therapy, did not provide any beneficial effect on the spermatogonial count.…”

Impacts of platinum-based chemotherapy on subsequent testicular function and fertility in boys with cancer

“…The finding of persistent azoospermia in men after platinum-based chemotherapy suggests damage to the spermatogonial stem cell (SSC) population, which is also the likely target for damage by platinum-based chemotherapy during childhood, leading to impairment of fertility in adulthood. A reduced number of spermatogonia, including SSCs, has been reported in several recent studies involving histological examination of testicular biopsies in boys with cancer ( Poganitsch-Korhonen et al , 2017 ; Stukenborg et al , 2018 ; Valli-Pulaski et al , 2019 ; Portela et al , 2020 ). However, these studies did not include data on the contribution of cisplatin to the germ cell loss.…”

The ameliorative effect of curcumin on cryptorchid and non-cryptorchid testes in induced unilateral cryptorchidism in albino rat: histological evaluation

“…In PCNA immunohistochemistry, control rats showed diffuse nuclear immunostaining in the spermatogenic cells in addition to the interstitial tissue. Thus, indicating healthy high proliferative capacity of the testicular tissue [28]. In GpIII, significant decrease in PCNA immunostained cells was noted as compared to GpI.…”