Spermatogonial stem cell autotransplantation and germline genomic editing: a future cure for spermatogenic failure and prevention of transmission of genomic diseases

Abstract

BACKGROUNDSubfertility 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 RATIONALEThe 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 METHODSWe 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.OUTCOMESCurrent 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 IMPLICATIONSSSCT 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 ...

The antineoplastic busulphan impairs peritubular and Leydig cells, and vitamin B12 stimulates spermatogonia proliferation and prevents busulphan-induced germ cell death

“…In the testes, the spermatogonial cells are vulnerable to cytotoxic agents and may be depleted [13]. Thus, cryopreservation, sperm retrieval techniques and spermatogonial stem cell transplantation (SSCT) have been tested to preserve testicular function and fertility [7,14,15].…”

Reelin regulates male mouse reproductive capacity via the sertoli cells

“…As the key “nurse cells,” sertoli cells play various roles in testes. The epithelial cycle is prefigured in the sertoli cells at the embryonic stage in murine testes . The loss of key genes in sertoli cells leads to the impairment of the SSC niche, thereby causing germ cell exhaustion by attenuating chemokine signaling .…”

“…The epithelial cycle is prefigured in the sertoli cells at the embryonic stage in murine testes. 27 The loss of key genes in sertoli cells leads to the impairment of the SSC niche, thereby causing germ cell exhaustion by attenuating chemokine signaling. 28 Assuming that sertoli cells serve as potential targets in reeler mice, we tested the CXCL12/CXCR4 signaling pathway.…”

Stem Cells: Ray of Hope in Infertility

“…This application involves transplantation of SSCs into the seminiferous tubules via the efferent duct or rete testis. Post-transplantation colonization, self-renewal and differentiation of SSCs occur in seminiferous tubules and normal spermatogenesis ensues [4][5][6].…”