Yamada Makiko, De Chiara Letizia, Seandel Marco
Joan and Sanford I Weill Medical College of Cornell University, 12295, Surgery, New York, New York, United States ;
Stem Cells Dev. 2016 Oct;25(20):1483-1494. doi: 10.1089/scd.2016.0210. Epub 2016 Sep 5.
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.
精原干细胞（SSCs）通过持续自我更新和分化，在雄性整个生殖生命过程中维持哺乳动物的精子发生，最终分化为精子。SSCs可以长期培养，并在移植回体内天然微环境后恢复精子发生。传统上，SSC研究主要集中在男性不育方面，在细胞重编程方面的研究较少。然而，随着全基因组测序技术的出现，人类研究发现了男性生殖系中出现的多种致病等位基因。已显示一部分新生点突变（DNMs）起源于SSCs，并导致儿童先天性疾病。本综述描述了已知或疑似由SSCs突变驱动的单基因疾病（如Apert综合征）和复杂疾病。我们认为SSC培养是研究这些疾病起源和机制的合适模型。最后，我们讨论了基于SSC技术未来临床应用的策略，从通过精子筛查检测突变负荷到体外基因校正。
