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Molecular Basis of Fertility Preservation and Restoration
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Molecular Basis of Fertility Preservation and Restoration

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 74802

Special Issue Editor

Prof. Christine Wyns

E-Mail Website
Guest Editor
Gynecology-Andrology department, Cliniques universitaires Saint-Luc, Medical School, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium
Interests: fertility preservation; spermatogonial stem cells; spermatogenesis; in vitro maturation; transplantation; immature testicular tissue; tissue engineering; regenerative medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fertility preservation both on the male and female side is an exciting field, especially considering the urgent current need to find methods that allow parenthood with one’s own genetic background when gonadotoxic therapies at risk of permanent infertility are applied or when a genetic condition responsible for infertility or loss of fertility over time is present.

Numerous approaches to preserve and restore fertility are under investigation and, with the perspective of a clinical application, a better understanding of current achievements at the cellular and molecular levels is awaited. Some strategies rely on using cryopreserved gonadal tissue or cells, such as in vitro germ cell maturation or cell and tissue transplantation, while others focus on using alternative sources of stem cells or on protecting in situ germ cells from gonadotoxicity. To facilitate preclinical studies, improved knowledge on molecular markers for developing germ cells could prove useful. This Special Issue therefore focuses on current developments in the field of fertility preservation and on perspectives for fertility restoration in humans. We welcome original research and review articles.

Prof. Christine Wyns
Guest Editor

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Keywords

  • fertility preservation
  • spermatogonia
  • stem cells
  • ovarian tissue
  • in vitro maturation
  • transplantation
  • miRNA
  • germ cells
  • single cell transcriptome
  • induced pluripotent stem cells

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Published Papers (17 papers)

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Research

Jump to: Review

18 pages, 2488 KiB  
Article
A Role for Exchange of Extracellular Vesicles in Porcine Spermatogonial Co-Culture
by Shiama Thiageswaran, Heather Steele, Anna Laura Voigt and Ina Dobrinski
Int. J. Mol. Sci. 2022, 23(9), 4535; https://doi.org/10.3390/ijms23094535 - 20 Apr 2022
Cited by 9 | Viewed by 2575
Abstract
Spermatogonial stem cells (SSCs) provide the basis for lifelong male fertility through self-renewal and differentiation. Prepubertal male cancer patients may be rendered infertile by gonadotoxic chemotherapy and, unlike sexually mature men, cannot store sperm. Alternatively, testicular biopsies taken prior to treatment may be [...] Read more.
Spermatogonial stem cells (SSCs) provide the basis for lifelong male fertility through self-renewal and differentiation. Prepubertal male cancer patients may be rendered infertile by gonadotoxic chemotherapy and, unlike sexually mature men, cannot store sperm. Alternatively, testicular biopsies taken prior to treatment may be used to restore fertility in adulthood. Testicular SSC populations are limited, and in vitro culture systems are required to increase numbers of SSCs for treatment, demanding culture systems for SSC propagation. Using the pig as a non-rodent model, we developed culture systems to expand spermatogonia from immature testis tissue, comparing different feeders (Sertoli cells, peritubular myoid cells (PMCs) and pig fetal fibroblasts (PFFs)). Spermatogonia co-cultured with Sertoli cells, PMCs and PFFs had comparable rates of proliferation and apoptosis. To elucidate the mechanism behind the beneficial nature of feeder layers, we investigated the role of extracellular vesicles in crosstalk between spermatogonia and feeder cells. Sertoli cell-released exosomes are incorporated by spermatogonia, and inhibition of exosomal release reduces spermatogonial proliferation. Together, these results show that PMCs, PFFs and Sertoli cells promote spermatogonial proliferation in co-culture, with exosomal exchange representing one possible mechanism. Further characterization of exosomal cargo may ultimately allow the development of feeder-free culture systems for clinical use. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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18 pages, 8565 KiB  
Article
In Vitro Propagation of XXY Undifferentiated Mouse Spermatogonia: Model for Fertility Preservation in Klinefelter Syndrome Patients
by Guillermo Galdon, Nicholas A. Deebel, Nima Pourhabibi Zarandi, Mark J. Pettenati, Stanley Kogan, Christina Wang, Ronald S. Swerdloff, Anthony Atala, Yanhe Lue and Hooman Sadri-Ardekani
Int. J. Mol. Sci. 2022, 23(1), 173; https://doi.org/10.3390/ijms23010173 - 24 Dec 2021
Cited by 6 | Viewed by 3289
Abstract
Klinefelter syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (usually XXY), and spermatogonial stem cell (SSC) loss in their early life. Affecting 1 out of every 650 males born, KS is the most common genetic cause of male infertility, and [...] Read more.
Klinefelter syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (usually XXY), and spermatogonial stem cell (SSC) loss in their early life. Affecting 1 out of every 650 males born, KS is the most common genetic cause of male infertility, and new fertility preservation strategies are critically important for these patients. In this study, testes from 41, XXY prepubertal (3-day-old) mice were frozen-thawed. Isolated testicular cells were cultured and characterized by qPCR, digital PCR, and flow cytometry analyses. We demonstrated that SSCs survived and were able to be propagated with testicular somatic cells in culture for up to 120 days. DNA fluorescent in situ hybridization (FISH) showed the presence of XXY spermatogonia at the beginning of the culture and a variety of propagated XY, XX, and XXY spermatogonia at the end of the culture. These data provide the first evidence that an extra sex chromosome was lost during innate SSC culture, a crucial finding in treating KS patients for preserving and propagating SSCs for future sperm production, either in vitro or in vivo. This in vitro propagation system can be translated to clinical fertility preservation for KS patients. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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15 pages, 2657 KiB  
Article
The Proliferation of Pre-Pubertal Porcine Spermatogonia in Stirred Suspension Bioreactors Is Partially Mediated by the Wnt/β-Catenin Pathway
by Sadman Sakib, Anna Voigt, Nathalia de Lima e Martins Lara, Lin Su, Mark Ungrin, Derrick Rancourt and Ina Dobrinski
Int. J. Mol. Sci. 2021, 22(24), 13549; https://doi.org/10.3390/ijms222413549 - 17 Dec 2021
Cited by 3 | Viewed by 2185
Abstract
Male survivors of childhood cancer are at risk of suffering from infertility in adulthood because of gonadotoxic chemotherapies. For adult men, sperm collection and preservation are routine procedures prior to treatment; however, this is not an option for pre-pubertal children. From young boys, [...] Read more.
Male survivors of childhood cancer are at risk of suffering from infertility in adulthood because of gonadotoxic chemotherapies. For adult men, sperm collection and preservation are routine procedures prior to treatment; however, this is not an option for pre-pubertal children. From young boys, a small biopsy may be taken before chemotherapy, and spermatogonia may be propagated in vitro for future transplantation to restore fertility. A robust system that allows for scalable expansion of spermatogonia within a controlled environment is therefore required. Stirred suspension culture has been applied to different types of stem cells but has so far not been explored for spermatogonia. Here, we report that pre-pubertal porcine spermatogonia proliferate more in bioreactor suspension culture, compared with static culture. Interestingly, oxygen tension provides an avenue to modulate spermatogonia status, with culture under 10% oxygen retaining a more undifferentiated state and reducing proliferation in comparison with the conventional approach of culturing under ambient oxygen levels. Spermatogonia grown in bioreactors upregulate the Wnt/ β-catenin pathway, which, along with enhanced gas and nutrient exchange observed in bioreactor culture, may synergistically account for higher spermatogonia proliferation. Therefore, stirred suspension bioreactors provide novel platforms to culture spermatogonia in a scalable manner and with minimal handling. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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14 pages, 3712 KiB  
Article
Ovarian Follicles Rescued 3 Days after Cyclophosphamide Treatment in Adolescent Mice: An Experimental Study Aiming at Maximizing Methods for Fertility Preservation through In Vitro Follicle Culture
by Amandine Anastácio, Max Waterstone, Xia Hao, Catherine Poirot and Kenny A. Rodriguez-Wallberg
Int. J. Mol. Sci. 2019, 20(24), 6190; https://doi.org/10.3390/ijms20246190 - 7 Dec 2019
Cited by 3 | Viewed by 5345
Abstract
There is currently a lack of knowledge about the feasibility of performing procedures for fertility preservation after chemotherapy treatment has been initiated. In this experimental controlled study using adolescent mice, we aimed to investigate if the chance of rescuing and growing in vitro [...] Read more.
There is currently a lack of knowledge about the feasibility of performing procedures for fertility preservation after chemotherapy treatment has been initiated. In this experimental controlled study using adolescent mice, we aimed to investigate if the chance of rescuing and growing in vitro secondary follicles (SeF) would be affected three days after a single injection of cyclophosphamide (CPA). The main outcomes included were: (1) The number of SeF with good morphologic quality obtained per ovary 3 days after CPA injection, (2) SeF development in culture, (3) small follicle density (SFD) on histology, and (4) apoptosis markers, including terminal deoxynucleotidyl transferase dUTP nick end-labelling (TUNEL), mRNA expression, and distribution of p 53 upregulated modulator of apoptosis (Puma) and phosphatase and tensin homolog (Pten). We found a 60% reduction of SeF obtained per ovary in all CPA-treated groups vs. controls. However, in vitro survival rates at culture day 12 and antrum formation were similar among all groups. On histology, SFD was only significantly reduced in the high CPA dose group. Apoptotic cells were mainly found in large growing follicles of CPA groups. Our study indicates the feasibility of SeF isolation and in vitro follicle culture 3 days following CPA treatment and a still preserved SFD, particularly following a low-dose CPA treatment. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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18 pages, 4160 KiB  
Article
Significant Benefits of Nanoparticles Containing a Necrosis Inhibitor on Mice Testicular Tissue Autografts Outcomes
by Federico Del Vento, Maxime Vermeulen, Bernard Ucakar, Jonathan Poels, Anne des Rieux and Christine Wyns
Int. J. Mol. Sci. 2019, 20(23), 5833; https://doi.org/10.3390/ijms20235833 - 20 Nov 2019
Cited by 16 | Viewed by 2526
Abstract
Fertility preservation for prepubertal boys relies exclusively on cryopreservation of immature testicular tissue (ITT) containing spermatogonia as the only cells with reproductive potential. Preclinical studies that used a nude mice model to evaluate the development of human transplanted ITT were characterized by important [...] Read more.
Fertility preservation for prepubertal boys relies exclusively on cryopreservation of immature testicular tissue (ITT) containing spermatogonia as the only cells with reproductive potential. Preclinical studies that used a nude mice model to evaluate the development of human transplanted ITT were characterized by important spermatogonial loss. We hypothesized that the encapsulation of testicular tissue in an alginate matrix supplemented with nanoparticles containing a necrosis inhibitor (NECINH-NPS) would improve tissue integrity and germ cells’ survival in grafts. We performed orthotopic autotransplantation of 1 mm³ testicular tissue fragments recovered form mice (aged 4–5 weeks). Fragments were either non-encapsulated, encapsulated in an alginate matrix, or encapsulated in an alginate matrix containing NECINH-NPs. Grafts were recovered 5- and 21-days post-transplantation. We evaluated tissue integrity (hematoxylin-eosin staining), germ cells survival (immunohistochemistry for promyelocytic leukemia zinc-finger, VASA, and protein-boule-like), apoptosis (immunohistochemistry for active-caspase 3), and lipid peroxidation (immunohistochemistry for malondialdehyde). NECINH-NPs significantly improved testicular tissue integrity and germ cells’ survival after 21 days. Oxidative stress was reduced after 5 days, regardless of nanoparticle incorporation. No effect on caspase-dependent apoptosis was observed. In conclusion, NECINH-NPs in an alginate matrix significantly improved tissue integrity and germ cells’ survival in grafts with the perspective of higher reproductive outcomes. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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Graphical abstract

13 pages, 3827 KiB  
Article
Blood Testis Barrier and Somatic Cells Impairment in a Series of 35 Adult Klinefelter Syndrome Patients
by Maria Grazia Giudice, Maxime Vermeulen and Christine Wyns
Int. J. Mol. Sci. 2019, 20(22), 5717; https://doi.org/10.3390/ijms20225717 - 14 Nov 2019
Cited by 21 | Viewed by 3356
Abstract
Klinefelter Syndrome (KS) is the most common genetic cause of infertility in men. Degeneration of the testicular tissue starts in utero and accelerates at puberty with hyalinisation of seminiferous tubules, spermatogonia apoptosis and germ cell maturation arrest. Therefore, fertility preservation in young KS [...] Read more.
Klinefelter Syndrome (KS) is the most common genetic cause of infertility in men. Degeneration of the testicular tissue starts in utero and accelerates at puberty with hyalinisation of seminiferous tubules, spermatogonia apoptosis and germ cell maturation arrest. Therefore, fertility preservation in young KS boys has been proposed, although this measure is still debated due to insufficient knowledge of the pathophysiology of the disease. To better understand the underlying mechanisms of testicular failure and germ cell loss, we analysed functional and morphological alterations in the somatic compartment of KS testis, i.e., Sertoli cells, including the blood–testis barrier (BTB) and Leydig cells (LC). We compared three populations: 35 KS 47,XXY non-mosaic patients, 28 Sertoli-cell-only (SCO) syndrome patients and 9 patients with normal spermatogenesis. In KS patients the expression of BTB proteins connexin-43 and claudin-11 assessed with a semi-quantitative scoring system appeared significantly reduced with a disorganised pattern. A significant reduction in seminiferous tubules expressing androgen receptors (AR) was observed in KS compared to normal spermatogenesis controls. INSL3 expression, a marker of LC maturation, was also significantly reduced in KS compared to patients with normal spermatogenesis or SCO. Hence, the somatic compartment impairment in KS could be involved in degeneration of seminiferous tubules. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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20 pages, 4035 KiB  
Article
Generation of Organized Porcine Testicular Organoids in Solubilized Hydrogels from Decellularized Extracellular Matrix
by Maxime Vermeulen, Federico Del Vento, Marc Kanbar, Sébastien Pyr dit Ruys, Didier Vertommen, Jonathan Poels and Christine Wyns
Int. J. Mol. Sci. 2019, 20(21), 5476; https://doi.org/10.3390/ijms20215476 - 3 Nov 2019
Cited by 53 | Viewed by 6490
Abstract
Cryopreservation of immature testicular tissue (ITT) prior to chemo/radiotherapy is now ethically accepted and is currently the only way to preserve fertility of prepubertal boys about to undergo cancer therapies. So far, three-dimensional culture of testicular cells isolated from prepubertal human testicular tissue [...] Read more.
Cryopreservation of immature testicular tissue (ITT) prior to chemo/radiotherapy is now ethically accepted and is currently the only way to preserve fertility of prepubertal boys about to undergo cancer therapies. So far, three-dimensional culture of testicular cells isolated from prepubertal human testicular tissue was neither efficient nor reproducible to obtain mature spermatozoa, and ITT transplantation is not a safe option when there is a risk of cancer cell contamination of the testis. Hence, generation of testicular organoids (TOs) after cell selection is a novel strategy aimed at restoring fertility in these patients. Here, we created TOs using hydrogels developed from decellularized porcine ITT and compared cell numbers, organization and function to TOs generated in collagen only hydrogel. Organotypic culture of porcine ITT was used as a control. Rheological and mass spectrometry analyses of both hydrogels highlighted differences in terms of extracellular matrix stiffness and composition, respectively. Sertoli cells (SCs) and germ cells (GCs) assembled into seminiferous tubule-like structures delimited by a basement membrane while Leydig cells (LCs) and peritubular cells localized outside. TOs were maintained for 45 days in culture and secreted stem cell factor and testosterone demonstrating functionality of SCs and LCs, respectively. In both TOs GC numbers decreased and SC numbers increased. However, LC numbers decreased significantly in the collagen hydrogel TOs (p < 0.05) suggesting a better preservation of growth factors within TOs developed from decellularized ITT and thus a better potential to restore the reproductive capacity. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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14 pages, 4846 KiB  
Article
Xeno-Free Propagation of Spermatogonial Stem Cells from Infant Boys
by Lihua Dong, Murat Gul, Simone Hildorf, Susanne Elisabeth Pors, Stine Gry Kristensen, Eva R. Hoffmann, Dina Cortes, Jorgen Thorup and Claus Yding Andersen
Int. J. Mol. Sci. 2019, 20(21), 5390; https://doi.org/10.3390/ijms20215390 - 29 Oct 2019
Cited by 16 | Viewed by 3729
Abstract
Spermatogonial stem cell (SSC) transplantation therapy is a promising strategy to renew spermatogenesis for prepubertal boys whose fertility is compromised. However, propagation of SSCs is required due to a limited number of SSCs in cryopreserved testicular tissue. This propagation must be done under [...] Read more.
Spermatogonial stem cell (SSC) transplantation therapy is a promising strategy to renew spermatogenesis for prepubertal boys whose fertility is compromised. However, propagation of SSCs is required due to a limited number of SSCs in cryopreserved testicular tissue. This propagation must be done under xeno-free conditions for clinical application. SSCs were propagated from infant testicular tissue (7 mg and 10 mg) from two boys under xeno-free conditions using human platelet lysate and nutrient source. We verified SSC-like cell clusters (SSCLCs) by quantitative real-time polymerase chain reaction (PCR) and immune-reaction assay using the SSC markers undifferentiated embryonic cell transcription factor 1 (UTF1), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), GDNF receptor alpha-1 (GFRα-1) Fα and promyelocytic leukaemia zinc finger protein (PLZF). The functionality of the propagated SSCs was investigated by pre-labelling using green fluorescent Cell Linker PKH67 and xeno-transplantation of the SSCLCs into busulfan-treated, therefore sterile, immunodeficient mice. SSC-like cell clusters (SSCLCs) appeared after 2 weeks in primary passage. The SSCLCs were SSC-like as the UTF1, UCHL1, GFRα1 and PLZF were all positive. After 2.5 months’ culture period, a total of 13 million cells from one sample were harvested for xenotransplantation. Labelled human propagated SSCs were identified and verified in mouse seminiferous tubules at 3–6 weeks, confirming that the transplanted cells contain SSCLCs. The present xeno-free clinical culture protocol allows propagation of SSCs from infant boys. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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22 pages, 7918 KiB  
Article
Vitamin E but Not GSH Decreases Reactive Oxygen Species Accumulation and Enhances Sperm Production during In Vitro Maturation of Frozen-Thawed Prepubertal Mouse Testicular Tissue
by Brahim Arkoun, Ludovic Galas, Ludovic Dumont, Aurélie Rives, Justine Saulnier, Marion Delessard, Christine Rondanino and Nathalie Rives
Int. J. Mol. Sci. 2019, 20(21), 5380; https://doi.org/10.3390/ijms20215380 - 29 Oct 2019
Cited by 20 | Viewed by 3760
Abstract
Freezing–thawing procedures and in vitro culture conditions are considered as a source of stress associated with increased reactive oxygen species (ROS) generation, leading to a damaged cell aerobic metabolism and consequently to oxidative stress. In the present study, we sought to investigate whether [...] Read more.
Freezing–thawing procedures and in vitro culture conditions are considered as a source of stress associated with increased reactive oxygen species (ROS) generation, leading to a damaged cell aerobic metabolism and consequently to oxidative stress. In the present study, we sought to investigate whether vitamin E (Vit E) or reduced glutathione (GSH) enhances sperm production by decreasing ROS accumulation during in vitro maturation of prepubertal mice testes. Testes of prepubertal mice were cryopreserved using a freezing medium supplemented or not supplemented with Vit E and were cultured after thawing. In presence of Rol alone in culture medium, frozen-thawed (F-T) testicular tissues exhibited a higher ROS accumulation than fresh tissue during in vitro culture. However, Vit E supplementation in freezing, thawing, and culture media significantly decreased cytoplasmic ROS accumulation in F-T testicular tissue during in vitro maturation when compared with F-T testicular tissue cultured in the presence of Rol alone, whereas GSH supplementation in culture medium significantly increased ROS accumulation associated with cytolysis and tissue disintegration. Vit E but not GSH promoted a better in vitro sperm production and was a suitable ROS scavenger and effective molecule to improve the yield of in vitro spermatogenesis from F-T prepubertal mice testes. The prevention of oxidative stress in the cytoplasmic compartment should be regarded as a potential strategy for improving testicular tissue viability and functionality during the freeze–thaw procedure and in vitro maturation. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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13 pages, 1989 KiB  
Article
Answer to Controversy: miR-10a Replacement Approaches Do Not Offer Protection against Chemotherapy-Induced Gonadotoxicity in Mouse Model
by Chrysanthi Alexandri, Christina-Anna Stratopoulou and Isabelle Demeestere
Int. J. Mol. Sci. 2019, 20(19), 4958; https://doi.org/10.3390/ijms20194958 - 8 Oct 2019
Cited by 4 | Viewed by 3903
Abstract
It is well known that chemotherapeutic agents may lead to premature ovarian failure and infertility. Therefore, fertility preservation is highly recommended for female cancer survivors. Despite the currently available techniques, new, non-invasive methods need to be developed to protect the ovarian follicles during [...] Read more.
It is well known that chemotherapeutic agents may lead to premature ovarian failure and infertility. Therefore, fertility preservation is highly recommended for female cancer survivors. Despite the currently available techniques, new, non-invasive methods need to be developed to protect the ovarian follicles during oncological treatments. MicroRNAs can be effective tools in this field, as they alter their expression during chemotherapy exposure, and hence they can be useful to minimize the off-target toxicity. Previously, we identified several miRNAs with an important role in newborn mouse ovaries exposed to chemotherapy; among them, the miR-10a was one of the most downregulated miRNAs. Given the controversial role of miR-10a in the ovarian function, we decided to investigate its implication in chemotherapy-induced gonadotoxicity. The downregulated levels of miR-10a were restored by a liposome system conjugated with a mimic miR-10a, and the overexpressed miR-10a prevented the upregulation of the targeted gene, phosphatase and tensin homolog (Pten). The apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) Assay and Bax expression quantification, while histological studies were also performed to evaluate the follicle count and development. Our results showed that the miR-10a replacement could not protect the ovaries from chemotherapy-induced apoptosis, whereas the targeting of Pten may affect the follicle activation via the phosphoinositide 3-kinase (PI3K)/PTEN/protein kinase B (AKT) pathway. Consequently, the application of miR-10a in fertility preservation is not recommended, and the role of miR-10a needs to be further elucidated. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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Review

Jump to: Research

23 pages, 899 KiB  
Review
Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility
by Marion Delessard, Justine Saulnier, Aurélie Rives, Ludovic Dumont, Christine Rondanino and Nathalie Rives
Int. J. Mol. Sci. 2020, 21(4), 1454; https://doi.org/10.3390/ijms21041454 - 20 Feb 2020
Cited by 65 | Viewed by 7727
Abstract
Over the last decade, the number of cancer survivors has increased thanks to progress in diagnosis and treatment. Cancer treatments are often accompanied by adverse side effects depending on the age of the patient, the type of cancer, the treatment regimen, and the [...] Read more.
Over the last decade, the number of cancer survivors has increased thanks to progress in diagnosis and treatment. Cancer treatments are often accompanied by adverse side effects depending on the age of the patient, the type of cancer, the treatment regimen, and the doses. The testicular tissue is very sensitive to chemotherapy and radiotherapy. This review will summarize the epidemiological and experimental data concerning the consequences of exposure to chemotherapy during the prepubertal period or adulthood on spermatogenic progression, sperm production, sperm nuclear quality, and the health of the offspring. Studies concerning the gonadotoxicity of anticancer drugs in adult survivors of childhood cancer are still limited compared with those concerning the effects of chemotherapy exposure during adulthood. In humans, it is difficult to evaluate exactly the toxicity of chemotherapeutic agents because cancer treatments often combine chemotherapy and radiotherapy. Thus, it is important to undertake experimental studies in animal models in order to define the mechanism involved in the drug gonadotoxicity and to assess the effects of their administration alone or in combination on immature and mature testis. These data will help to better inform cancer patients after recovery about the risks of chemotherapy for their future fertility and to propose fertility preservation options. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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13 pages, 1715 KiB  
Review
Human Pluripotent Stem Cells in Reproductive Science—A Comparison of Protocols Used to Generate and Define Male Germ Cells from Pluripotent Stem Cells
by Magdalena Kurek, Halima Albalushi, Outi Hovatta and Jan-Bernd Stukenborg
Int. J. Mol. Sci. 2020, 21(3), 1028; https://doi.org/10.3390/ijms21031028 - 4 Feb 2020
Cited by 6 | Viewed by 3291
Abstract
Globally, fertility-related issues affect around 15% of couples. In 20%–30% of cases men are solely responsible, and they contribute in around 50% of all cases. Hence, understanding of in vivo germ-cell specification and exploring different angles of fertility preservation and infertility intervention are [...] Read more.
Globally, fertility-related issues affect around 15% of couples. In 20%–30% of cases men are solely responsible, and they contribute in around 50% of all cases. Hence, understanding of in vivo germ-cell specification and exploring different angles of fertility preservation and infertility intervention are considered hot topics nowadays, with special focus on the use of human pluripotent stem cells (hPSCs) as a source of in vitro germ-cell generation. However, the generation of male germ cells from hPSCs can currently be considered challenging, making a judgment on the real perspective of these innovative approaches difficult. Ever since the first spontaneous germ-cell differentiation studies, using human embryonic stem cells, various strategies, including specific co-cultures, gene over-expression, and addition of growth factors, have been applied for human germ-cell derivation. In line with the variety of differentiation methods, the outcomes have ranged from early and migratory primordial germ cells up to post-meiotic spermatids. This variety of culture approaches and cell lines makes comparisons between protocols difficult. Considering the diverse strategies and outcomes, we aim in this mini-review to summarize the literature regarding in vitro derivation of human male germ cells from hPSCs, while keeping a particular focus on the culture methods, growth factors, and cell lines used. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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22 pages, 1245 KiB  
Review
Contribution of Single-Cell Transcriptomics to the Characterization of Human Spermatogonial Stem Cells: Toward an Application in Male Fertility Regenerative Medicine?
by Anne-Sophie Gille, Clémentine Lapoujade, Jean-Philippe Wolf, Pierre Fouchet and Virginie Barraud-Lange
Int. J. Mol. Sci. 2019, 20(22), 5773; https://doi.org/10.3390/ijms20225773 - 16 Nov 2019
Cited by 6 | Viewed by 3724
Abstract
Ongoing progress in genomic technologies offers exciting tools that can help to resolve transcriptome and genome-wide DNA modifications at single-cell resolution. These methods can be used to characterize individual cells within complex tissue organizations and to highlight various molecular interactions. Here, we will [...] Read more.
Ongoing progress in genomic technologies offers exciting tools that can help to resolve transcriptome and genome-wide DNA modifications at single-cell resolution. These methods can be used to characterize individual cells within complex tissue organizations and to highlight various molecular interactions. Here, we will discuss recent advances in the definition of spermatogonial stem cells (SSC) and their progenitors in humans using the single-cell transcriptome sequencing (scRNAseq) approach. Exploration of gene expression patterns allows one to investigate stem cell heterogeneity. It leads to tracing the spermatogenic developmental process and its underlying biology, which is highly influenced by the microenvironment. scRNAseq already represents a new diagnostic tool for the personalized investigation of male infertility. One may hope that a better understanding of SSC biology could facilitate the use of these cells in the context of fertility preservation of prepubertal children, as a key component of regenerative medicine. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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17 pages, 1327 KiB  
Review
The Impact of Chemotherapy on the Ovaries: Molecular Aspects and the Prevention of Ovarian Damage
by Charlotte Sonigo, Isabelle Beau, Nadine Binart and Michaël Grynberg
Int. J. Mol. Sci. 2019, 20(21), 5342; https://doi.org/10.3390/ijms20215342 - 27 Oct 2019
Cited by 46 | Viewed by 5707
Abstract
Cancer treatment, such as chemotherapy, induces early ovarian follicular depletion and subsequent infertility. In order to protect gametes from the gonadotoxic effects of chemotherapy, several fertility preservation techniques—such as oocyte or embryo cryopreservation with or without ovarian stimulation, or cryopreservation of the ovarian [...] Read more.
Cancer treatment, such as chemotherapy, induces early ovarian follicular depletion and subsequent infertility. In order to protect gametes from the gonadotoxic effects of chemotherapy, several fertility preservation techniques—such as oocyte or embryo cryopreservation with or without ovarian stimulation, or cryopreservation of the ovarian cortex—should be considered. However, these methods may be difficult to perform, and the future use of cryopreserved germ cells remains uncertain. Therefore, improving the methods currently available and developing new strategies to preserve fertility represent major challenges in the area of oncofertility. Animal and ovarian culture models have been used to decipher the effects of different cytotoxic agents on ovarian function and several theories regarding chemotherapy gonadotoxicity have been raised. For example, cytotoxic agents might (i) have a direct detrimental effect on the DNA of primordial follicles constituting the ovarian reserve and induce apoptosis; (ii) induce a massive growth of dormant follicles, which are then destroyed; or (ii) induce vascular ovarian damage. Thanks to improvements in the understanding of the mechanisms involved, a large number of studies have been carried out to develop molecules limiting the negative impact of chemotherapy on the ovaries. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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12 pages, 436 KiB  
Review
Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia
by Zaza Abidin and Eileen P. Treacy
Int. J. Mol. Sci. 2019, 20(20), 5236; https://doi.org/10.3390/ijms20205236 - 22 Oct 2019
Cited by 12 | Viewed by 5034
Abstract
Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12). Primary ovarian insufficiency (POI) is the most common long-term complication experienced by females with CG, presenting with hypergonadotrophic [...] Read more.
Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12). Primary ovarian insufficiency (POI) is the most common long-term complication experienced by females with CG, presenting with hypergonadotrophic hypoestrogenic infertility affecting at least 80% of females despite new-born screening and lifelong galactose dietary restriction. In this review, we describe the hypothesized pathophysiology of POI from CG, implications of timing of the ovarian dysfunction, and the new horizons and future prospects for treatments and fertility preservation. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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21 pages, 1385 KiB  
Review
Oncofertility: Pharmacological Protection and Immature Testicular Tissue (ITT)-Based Strategies for Prepubertal and Adolescent Male Cancer Patients
by Elissavet Ntemou, Chrysanthi Alexandri, Pascale Lybaert, Ellen Goossens and Isabelle Demeestere
Int. J. Mol. Sci. 2019, 20(20), 5223; https://doi.org/10.3390/ijms20205223 - 21 Oct 2019
Cited by 17 | Viewed by 6923
Abstract
While the incidence of cancer in children and adolescents has significantly increased over the last decades, improvements made in the field of cancer therapy have led to an increased life expectancy for childhood cancer survivors. However, the gonadotoxic effect of the treatments may [...] Read more.
While the incidence of cancer in children and adolescents has significantly increased over the last decades, improvements made in the field of cancer therapy have led to an increased life expectancy for childhood cancer survivors. However, the gonadotoxic effect of the treatments may lead to infertility. Although semen cryopreservation represents the most efficient and safe fertility preservation method for males producing sperm, it is not feasible for prepubertal boys. The development of an effective strategy based on the pharmacological protection of the germ cells and testicular function during gonadotoxic exposure is a non-invasive preventive approach that prepubertal boys could benefit from. However, the progress in this field is slow. Currently, cryopreservation of immature testicular tissue (ITT) containing spermatogonial stem cells is offered to prepubertal boys as an experimental fertility preservation strategy by a number of medical centers. Several in vitro and in vivo fertility restoration approaches based on the use of ITT have been developed so far with autotransplantation of ITT appearing more promising. In this review, we discuss the pharmacological approaches for fertility protection in prepubertal and adolescent boys and the fertility restoration approaches developed on the utilization of ITT. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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14 pages, 3200 KiB  
Review
The Human Ovary and Future of Fertility Assessment in the Post-Genome Era
by Emna Ouni, Didier Vertommen and Christiani A. Amorim
Int. J. Mol. Sci. 2019, 20(17), 4209; https://doi.org/10.3390/ijms20174209 - 28 Aug 2019
Cited by 6 | Viewed by 4493
Abstract
Proteomics has opened up new avenues in the field of gynecology in the post-genome era, making it possible to meet patient needs more effectively and improve their care. This mini-review aims to reveal the scope of proteomic applications through an overview of the [...] Read more.
Proteomics has opened up new avenues in the field of gynecology in the post-genome era, making it possible to meet patient needs more effectively and improve their care. This mini-review aims to reveal the scope of proteomic applications through an overview of the technique and its applications in assisted procreation. Some of the latest technologies in this field are described in order to better understand the perspectives of its clinical applications. Proteomics seems destined for a promising future in gynecology, more particularly in relation to the ovary. Nevertheless, we know that reproductive biology proteomics is still in its infancy and major technical and ethical challenges must first be overcome. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration)
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