BACKGROUND Subfertility affects approximately 15% of all couples, and a severe male factor is identified in 17% of these couples. While the etiology of a severe male factor remains largely unknown, prior gonadotoxic treatment and genomic aberrations have been associated with this type of subfertility. Couples with a severe male factor can resort to ICSI, with either ejaculated spermatozoa (in case of oligozoospermia) or surgically retrieved testicular spermatozoa (in case of azoospermia) to generate their own biological children. Currently there is no direct treatment for azoospermia or oligozoospermia. Spermatogonial stem cell (SSC) autotransplantation (SSCT) is a promising novel clinical application currently under development to restore fertility in sterile childhood cancer survivors. Meanwhile, recent advances in genomic editing, especially the clustered regulatory interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) system, are likely to enable genomic rectification of human SSCs in the near future. OBJECTIVE AND RATIONALE The objective of this review is to provide insights into the prospects of the potential clinical application of SSCT with or without genomic editing to cure spermatogenic failure and to prevent transmission of genetic diseases. SEARCH METHODS We performed a narrative review using the literature available on PubMed not restricted to any publishing year on topics of subfertility, fertility treatments, (molecular regulation of) spermatogenesis and SSCT, inherited (genetic) disorders, prenatal screening methods, genomic editing and germline editing. For germline editing, we focussed on the novel CRISPR-Cas9 system. We included papers written in English only. OUTCOMES Current techniques allow propagation of human SSCs in vitro, which is indispensable to successful transplantation. This technique is currently being developed in a preclinical setting for childhood cancer survivors who have stored a testis biopsy prior to cancer treatment. Similarly, SSCT could be used to restore fertility in sterile adult cancer survivors. In vitro propagation of SSCs might also be employed to enhance spermatogenesis in oligozoospermic men and in azoospermic men who still have functional SSCs albeit in insufficient numbers. The combination of SSCT with genomic editing techniques could potentially rectify defects in spermatogenesis caused by genomic mutations or, more broadly, prevent transmission of genomic diseases to the offspring. In spite of the promising prospects, SSCT and germline genomic editing are not yet clinically applicable and both techniques require optimization at various levels. WIDER IMPLICATIONS SSCT with or without genomic editing could potentially be used to restore fertility in cancer survivors to treat couples with a severe male factor and to prevent the paternal transmission of diseases. This will potentially allow these couples to have their own biological children. Technical development is progressing rapidly, and ethical reflection and societal debate on the use of SSCT with or without genomic editing is pressing.

中文翻译：

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精原干细胞自体移植和种系基因组编辑：未来治疗生精失败和预防基因组疾病传播的方法。

背景技术生育不足影响所有夫妇中的约15％，并且在这些夫妇中的17％中发现了严重的男性因素。尽管严重的男性因素的病因学仍然是未知的，但先前的性腺毒性治疗和基因组畸变与这种类型的不育有关。患有严重男性因素的夫妇可以诉诸ICSI，通过射精的精子（如果是少精子症）或通过手术取回睾丸的精子（如果是无精子症）来生自己的亲生孩子。目前尚无直接治疗无精症或少精症的方法。精原干细胞（SSC）自体移植（SSCT）是一种有前途的新颖临床应用，目前正在开发中，以恢复无菌儿童期癌症幸存者的生育能力。同时，基因组编辑的最新进展，尤其是簇状调控间隔的短回文重复相关蛋白9（CRISPR-Cas9）系统，很可能在不久的将来使人类SSC的基因组校正成为可能。目的和理由本综述的目的是提供有关SSCT潜在临床应用前景的见解，无论是否进行基因组编辑以治疗生精功能衰竭和预防遗传疾病的传播，SSCT的潜在临床应用前景。搜索方法我们使用了发表于PubMed的文献进行了叙述性综述，该文献不限于任何出版年，涉及亚生育力，生育力治疗，精子发生和SSCT的分子调控，遗传（遗传）疾病，产前筛查方法，基因组编辑和种系编辑。对于种系编辑，我们专注于新型CRISPR-Cas9系统。我们只收录了用英语撰写的论文。结果目前的技术允许人类SSCs在体外繁殖，这对于成功的移植是必不可少的。该技术目前正在临床前开发中，用于在癌症治疗之前已经进行了睾丸活检的儿童癌症幸存者。同样，SSCT可用于恢复无菌成人癌症幸存者的生育能力。SSCs的体外繁殖也可用于增强少精症男性和无精症男性的精子发生能力，尽管数量不足，这些男性仍具有功能性SSC。SSCT与基因组编辑技术的结合可以潜在地纠正由基因组突变引起的精子发生缺陷，或更广泛地说，可以防止基因组疾病传播给后代。尽管前景广阔，SSCT和种系基因组编辑尚未在临床上应用，并且两种技术都需要在各个级别进行优化。对儿童的影响不论是否进行基因组编辑，SSCT均可用于恢复癌症幸存者的生育能力，以治疗具有严重男性因素的夫妇，并预防疾病的父系传播。这将有可能使这些夫妇有自己的亲生子女。技术发展日新月异，关于在有无基因组编辑的情况下使用SSCT的伦理思考和社会争论迫在眉睫。对儿童的影响不论是否进行基因组编辑，SSCT均可用于恢复癌症幸存者的生育能力，以治疗具有严重男性因素的夫妇并预防疾病的父亲传播。这将有可能使这些夫妇有自己的亲生子女。技术发展日新月异，关于在有无基因组编辑的情况下使用SSCT的伦理思考和社会争论迫在眉睫。对儿童的影响不论是否进行基因组编辑，SSCT均可用于恢复癌症幸存者的生育能力，以治疗具有严重男性因素的夫妇并预防疾病的父亲传播。这将有可能使这些夫妇有自己的亲生子女。技术发展日新月异，关于在有无基因组编辑的情况下使用SSCT的伦理思考和社会争论迫在眉睫。