Role of stem cells in fertility preservation: current insights

Maxime Vermeulen, Maria-Grazia Giudice, Federico Del Vento, Christine Wyns, Maxime Vermeulen, Maria-Grazia Giudice, Federico Del Vento, Christine Wyns

Abstract

While improvements made in the field of cancer therapy allow high survival rates, gonadotoxicity of chemo- and radiotherapy can lead to infertility in male and female pre- and postpubertal patients. Clinical options to preserve fertility before starting gonadotoxic therapies by cryopreserving sperm or oocytes for future use with assisted reproductive technology (ART) are now applied worldwide. Cryopreservation of pre- and postpubertal ovarian tissue containing primordial follicles, though still considered experimental, has already led to the birth of healthy babies after autotransplantation and is performed in an increasing number of centers. For prepubertal boys who do not produce gametes ready for fertilization, cryopreservation of immature testicular tissue (ITT) containing spermatogonial stem cells may be proposed as an experimental strategy with the aim of restoring fertility. Based on achievements in nonhuman primates, autotransplantation of ITT or testicular cell suspensions appears promising to restore fertility of young cancer survivors. So far, whether in two- or three-dimensional culture systems, in vitro maturation of immature male and female gonadal cells or tissue has not demonstrated a capacity to produce safe gametes for ART. Recently, primordial germ cells have been generated from embryonic and induced pluripotent stem cells, but further investigations regarding efficiency and safety are needed. Transplantation of mesenchymal stem cells to improve the vascularization of gonadal tissue grafts, increase the colonization of transplanted cells, and restore the damaged somatic compartment could overcome the current limitations encountered with transplantation.

Keywords: fertility restoration; germ-line stem cells; in vitro maturation; mesenchymal stem cells; spermatogonial stem cells; transplantation.

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flowchart of paper selection.
Figure 2
Figure 2
Classic mice model used for fertility restoration by SSC transplantation. (A) SSCs are located along the basement membrane of STs and surrounded by nursing Sertoli cells. Spermatogonia differentiate progressively into spermatozoa toward the lumina of STs. Myoid cells create a wall around the STs while Leydig cells reside in the testicular interstitium. (B) SSCs can be isolated and propagated in vitro. (C) Germ-cell depletion by busulfan treatment favors stem cell–niche colonization. (D) Transplantation of SSC to STs of germ cell-depleted mice to restore spermatogenesis. Abbreviations: SSC, spermatogonial stem cell; ST, seminiferous tubule.
Figure 3
Figure 3
Fertility preservation in males. Notes: As they do not produce sperm, prepubertal boys can benefit from cryopreservation of a testicular tissue biopsy that could be used in the future for: 1) SSC isolation and propagation, with a view to restoring fertility of the patient by transplantation into own STs or for IVM to produce competent sperm for ART; 2) IVM in organotypic or microfluidic culture systems, with the aim to obtain sperm usable in ART; and 3) transplantation back into the patient to induce maturation and generation of spermatozoa that can be recovered and used for ART. Alternatively, derivation of iPSCs from different sources of somatic cells could lead to generation of competent spermatozoa. *Processes that could be improved with use of MSCs. Red arrows represent techniques that are still considered experimental. Blue arrows indicate methods that are already implemented in clinical practice. Abbreviations: ART, assisted reproductive technology; iPSCs, induced pluripotent stem cells; ITT, immature testicular tissue; IVM, in vitro maturation; MSCs, mesenchymal stem cells; SSC, spermatogonial stem cell.
Figure 4
Figure 4
Fertility preservation in females. Notes: Women at reproductive age can cryopreserve oocytes or embryos with aim of using it in the future. Women who have no time for ovarian stimulation and prepubertal girls can cryopreserve ovarian tissue, which can be transplanted back to the patient to restore her fertility or to obtain competent oocytes for ART. Generation of competent oocytes by IVM of follicles originating from the cryopreserved tissue could also be an option. Treatment of women who developed a POF due to cancer therapy could potentially restore their ovarian functions and fertility. Alternatively, derivation of iPSCs from different sources of somatic cells could lead to generation of competent oocytes. *Processes that could be improved with use of MSCs. Red arrows represent techniques that are still considered experimental. Blue arrows indicate methods that are already implemented in clinical practice. Abbreviations: ART, assisted reproductive technology; iPSCs, induced pluripotent stem cells; IVM, in vitro maturation, MSCs, mesenchymal stem cells; POF, premature ovarian failure.

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