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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.


Related in: MedlinePlus

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).
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f1: 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).

Mentions: Furthermore, testes obtained from normal older males have more mutations in PAE genes, and the cells bearing mutations are arranged in a spatially clustered manner [90–93]. The clustering phenomenon is reminiscent of tumor expansion in somatic tissues and cannot be explained in statistical models by a local increase in hot-spot mutations. Thus, the simplest explanation is positive selection of PAE mutations in SSCs. That is, a PAE mutation may arise in a single SSC that acquires a selective growth advantage as compared with its wild-type neighbors (Fig. 1). Goriely and Wilkie termed this phenomenon “selfish spermatogonial selection” [84].


Spermatogonial Stem Cells: Implications for Genetic Disorders and Prevention
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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5035912&req=5

f1: 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).
Mentions: Furthermore, testes obtained from normal older males have more mutations in PAE genes, and the cells bearing mutations are arranged in a spatially clustered manner [90–93]. The clustering phenomenon is reminiscent of tumor expansion in somatic tissues and cannot be explained in statistical models by a local increase in hot-spot mutations. Thus, the simplest explanation is positive selection of PAE mutations in SSCs. That is, a PAE mutation may arise in a single SSC that acquires a selective growth advantage as compared with its wild-type neighbors (Fig. 1). Goriely and Wilkie termed this phenomenon “selfish spermatogonial selection” [84].

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