title: Spermatogonial stem cell autotransplantation and germline genomic editing: a future cure for spermatogenic failure and prevention of transmission of genomic diseases.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Callista L
authors.initials: CL
authors.lastname: Mulder
authors.affiliation: Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sabrina Z
authors.initials: SZ
authors.lastname: Jan
authors.affiliation: Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Struijk
authors.affiliation: Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Repping
authors.affiliation: Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands g.hamer@amc.uva.nl.
authors.forename: Geert
authors.initials: G
authors.lastname: Hamer
authors.affiliation: Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Ans M M
authors.initials: AM
authors.lastname: van Pelt
mesh_terms: D000072956:Adult Germline Stem Cells / Q000502:physiology / Q000637:transplantation*; D000072669:Gene Editing / Q000379:methods*; D006801:Humans; D007248:Infertility, Male / Q000628:therapy*; D008297:Male; D009369:Neoplasms / Q000150:complications; D013091:Spermatogenesis / Q000502:physiology*; D013093:Spermatogonia / Q000166:cytology*; D013094:Spermatozoa / Q000502:physiology*; D014182:Transplantation, Autologous
keywords: CRISPR-Cas9; germline editing; male infertility; male reproductive disorders; spermatogonial stem cell autotransplantation