Spermatogonial Stem Cells: Implications for Genetic Disorders and Prevention

Abstract

Spermatogonial stem cells (SSCs) propagate mammalian spermatogenesis throughout male reproductive life by continuously self-renewing and differentiating, ultimately, into sperm. SSCs can be cultured for long periods and restore spermatogenesis upon transplantation back into the native microenvironment in vivo. Conventionally, SSC research has been focused mainly on male infertility and, to a lesser extent, on cell reprogramming. With the advent of genome-wide sequencing technology, however, human studies have uncovered a wide range of pathogenic alleles that arise in the male germline. A subset of de novo point mutations (DNMs) was shown to originate in SSCs and cause congenital disorders in children. This review describes both monogenic diseases (e.g., Apert syndrome) and complex disorders that are either known or suspected to be driven by mutations in SSCs. We propose that SSC culture is a suitable model for studying the origin and mechanisms of these diseases. Lastly, we discuss strategies for future clinical implementation of SSC-based technology, from detecting mutation burden by sperm screening to gene correction in vitro.

FIG. 1.

Schematic representation of the paternal age effect hypothesis. De novo point mutations (DNMs) may occur in isolated spermatogonial stem cells (SSCs, red dots on the second testis) conferring an advantage to the mutant cells over the wild type cells. During the course of the years, the mutant cells subsequently take over the wild type cells leading to a clonal expansion and colonization of the testis tubules (red fragment in the third and fourth testes), increasing the possibility to pass those mutations to the offspring (red spermatozoa).

FIG. 2.

Lineage tracing reveals the long-term kinetics of labeled SSCs. (A) An example of lineage tracing. In this segment of seminiferous tubules, a single SSC (black diamond; six SSCs are shown in the segment) is being labeled after induction. Certain clones (eg, only two clones out of six in this case) self-renew and expand to occupy the long segment (black area), but the rest disappear over time. By applying mathematical models to this phenomenon, Klein and Simons proposed a neutral competition model, in which all stem cells have equal proliferation potential, but some stem cells are lost in a stochastic manner [113]. (B) Actual images of clonal expansion in the lineage tracing system using the Sox2-creER^T2 driver. Tamoxifen was administered to a Sox2-creER^T2; Rosa-tdTomato mouse at 7 weeks of age. Right after the induction, Sox2-creER^T2 driver labeled A_single SSCs (left). After a long period of chase, SSC progeny clonally expand to form a large colony (right). Some of the undifferentiated spermatogonia retained Gfrα1 expression, which is known to mark SSCs. Scale bars: 40 μm.