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Spermatogonial Stem Cells: Implications for Genetic Disorders and Prevention

View Article: PubMed Central - PubMed

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 germ line. A subset of de novo point mutations was shown to originate in SSCs and cause congenital disorders in children. This review describes both monogenic diseases (eg, 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.

No MeSH data available.


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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-creERT2 driver. Tamoxifen was administered to a Sox2-creERT2; Rosa-tdTomato mouse at 7 weeks of age. Right after the induction, Sox2-creERT2 driver labeled Asingle 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.
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f2: 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-creERT2 driver. Tamoxifen was administered to a Sox2-creERT2; Rosa-tdTomato mouse at 7 weeks of age. Right after the induction, Sox2-creERT2 driver labeled Asingle 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.

Mentions: To assess homeostatic behavior of SSCs in vivo, Nakagawa et al. first described life-long kinetics of mouse SSCs using genetic lineage tracing, as already mentioned [11]. In this study, it was demonstrated that stem cells are occasionally lost and compensated for by other stem cells that form larger sized clones over time. Indeed, using a similar lineage tracing setup in the mouse testis, we observed that certain SSC clones survive for more than 1 year, expanding their territories, but the remaining clones disappear (unpublished data) (Fig. 2). By analyzing SSC clonal dynamics using mathematical models, Klein and Simons proposed that neutral competition confers all stem cells with equal proliferation potential, but some stem cells are lost in a stochastic manner and are replaced by others [113].


Spermatogonial Stem Cells: Implications for Genetic Disorders and Prevention
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-creERT2 driver. Tamoxifen was administered to a Sox2-creERT2; Rosa-tdTomato mouse at 7 weeks of age. Right after the induction, Sox2-creERT2 driver labeled Asingle 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.
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f2: 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-creERT2 driver. Tamoxifen was administered to a Sox2-creERT2; Rosa-tdTomato mouse at 7 weeks of age. Right after the induction, Sox2-creERT2 driver labeled Asingle 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.
Mentions: To assess homeostatic behavior of SSCs in vivo, Nakagawa et al. first described life-long kinetics of mouse SSCs using genetic lineage tracing, as already mentioned [11]. In this study, it was demonstrated that stem cells are occasionally lost and compensated for by other stem cells that form larger sized clones over time. Indeed, using a similar lineage tracing setup in the mouse testis, we observed that certain SSC clones survive for more than 1 year, expanding their territories, but the remaining clones disappear (unpublished data) (Fig. 2). By analyzing SSC clonal dynamics using mathematical models, Klein and Simons proposed that neutral competition confers all stem cells with equal proliferation potential, but some stem cells are lost in a stochastic manner and are replaced by others [113].

View Article: PubMed Central - PubMed

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 germ line. A subset of de novo point mutations was shown to originate in SSCs and cause congenital disorders in children. This review describes both monogenic diseases (eg, 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.

No MeSH data available.


Related in: MedlinePlus