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Molecular Basis of Fertility Preservation and Restoration 2.0
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Molecular Basis of Fertility Preservation and Restoration 2.0

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 (27 January 2021) | Viewed by 17862

Special Issue Editor

Prof. Dr. Mahmoud Huleihel

E-Mail Website
Guest Editor
1. The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
2. The Center of Advanced Research and Education in Reproduction (CARER), Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
Interests: male infertility; male fertility preservation; in vitro development of spermatogenesis; chemotherapy/irradiation and male infertility; cytokines/growth factors in the testis; acute myeloid leukemia and male infertility; rhree-dimension (3D) in vitro culture systems and spermatogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is a second edition of the previous Special Issue "Molecular Basis of Fertility Preservation and Restoration (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/fertility)".

Fertility preservation, on both the male and female sides, 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 risking 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 needed. Some strategies rely on the use of cryopreserved gonadal tissue or cells, such as in vitro germ cell maturation or cell and tissue transplantation, while others focus on the use of 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. Both original research and review articles are welcomed.

Prof. Dr. Mahmoud Huleihel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • fertility preservation
  • spermatogonia
  • stem cells
  • ovarian tissue
  • in vitro maturation
  • transplantation
  • miRNA
  • germ cells
  • single-cell transcriptome
  • induced pluripotent stem cells
  • organ-on-chip (OoC)
  • organoids
  • microfluidic systems
  • germ cell transplantation
  • epigenetics

Related Special Issue

Published Papers (7 papers)

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Research

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13 pages, 2189 KiB  
Article
The Effects of Sperm and Seminal Fluid of Immunized Male Mice on In Vitro Fertilization and Surrogate Mother–Embryo Interaction
by Galina Vladimirovna Kontsevaya, Ludmila Alekseevna Gerlinskaya, Yury Mikhailovich Moshkin, Margarita Vladimirovna Anisimova, Aliya Konstantinovna Stanova, Tatyana Ivanovna Babochkina and Mikhail Pavlovich Moshkin
Int. J. Mol. Sci. 2021, 22(19), 10650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910650 - 30 Sep 2021
Cited by 1 | Viewed by 2028
Abstract
The latest vaccination campaign has actualized the potential impact of antigenic stimuli on reproductive functions. To address this, we mimicked vaccination’s effects by administering keyhole limpet hemocyanin (KLH ) to CD1 male mice and used their sperm for in vitro fertilization (IVF). Two-cell [...] Read more.
The latest vaccination campaign has actualized the potential impact of antigenic stimuli on reproductive functions. To address this, we mimicked vaccination’s effects by administering keyhole limpet hemocyanin (KLH ) to CD1 male mice and used their sperm for in vitro fertilization (IVF). Two-cell embryos after IVF with spermatozoa from control (C) or KLH-treated (Im) male mice were transferred to surrogate mothers mated with vasectomized control (C) or KLH-treated (Im) male mice, resulting in four experimental groups: C–C, Im–C, C–Im, and Im–Im. The pre-implantation losses were significantly lower in the Im–C group than in the C–Im group. At the same time, the resorption rates reduced markedly in the C–Im compared to the Im–C group. Embryo and placenta weights were significantly higher in the Im–Im group. Although the GM-CSF levels were lower in the amniotic fluid of the gestating surrogate mothers in the Im–Im group, they were strongly correlated with embryo mass. The number–size trade-off was only significant in the Im–Im group. This suggests a positive, cooperative effect of spermatozoa and seminal fluid from immune-primed males on embryo growth and the optimal distribution of surrogate mother maternal resources despite the negative impact of males’ antigenic challenge on the IVF success rate. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 2.0)
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16 pages, 6174 KiB  
Article
Involvement of Cytokines and Hormones in the Development of Spermatogenesis In Vitro from Spermatogonial Cells of Cyclophosphamide-Treated Immature Mice
by Ronnie Solomon, Ali AbuMadighem, Joseph Kapelushnik, Bat-Chen Amano, Eitan Lunenfeld and Mahmoud Huleihel
Int. J. Mol. Sci. 2021, 22(4), 1672; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041672 - 07 Feb 2021
Cited by 7 | Viewed by 2682
Abstract
Aggressive chemotherapy treatment may lead to male infertility. Prepubertal boys do not produce sperm at this age, however, they have spermatogonial stem cells in their testes. Here, we examined the effect of intraperitoneal injection of cyclophosphamide (CP) on the capacity of immature mice [...] Read more.
Aggressive chemotherapy treatment may lead to male infertility. Prepubertal boys do not produce sperm at this age, however, they have spermatogonial stem cells in their testes. Here, we examined the effect of intraperitoneal injection of cyclophosphamide (CP) on the capacity of immature mice (IM) to develop spermatogenesis in vivo and in vitro [using methylcellulose culture system (MCS)]. Our results show a significant decrease in testicular weight, total number of testicular cells, and the number of Sertoli, peritubular, premeiotic, and meiotic/post-meiotic cells, but an increase in the percentages of damaged seminiferous tubules in CP-treated IM compared to control. The functionality of Sertoli cells was significantly affected. The addition of testosterone to isolated cells from seminiferous tubules of CP-treated IM significantly increased the percentages of premeiotic (CD9-positive cells) and meiotic/post-meiotic cells (ACROSIN-positive cells) developed in MCS compared to control. The addition of FSH did not affect developed cells in MCS compared to control, but in combination with testosterone, it significantly decreased the percentages of CD9-positive cells and ACROSIN-positive cells. The addition of IL-1 did not affect developed cells in MCS compared to control, but in combination with testosterone, it significantly increased the percentages of VASA-positive cells and BOULE-positive cells compared to IL-1 or testosterone. Addition of TNF significantly increased only CD9-positive cells in MCS compared to control, but in combination with testosterone, it significantly decreased ACROSIN-positive cells compared to testosterone. Our results show a significant impairment of spermatogenesis in the testes of CP-treated IM, and that spermatogonial cells from these mice proliferate and differentiate to meiotic/post-meiotic cells under in vitro culture conditions. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 2.0)
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12 pages, 1181 KiB  
Article
Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary
by Luca Mattiello, Giulia Pucci, Francesco Marchetti, Marc Diederich and Stefania Gonfloni
Int. J. Mol. Sci. 2021, 22(3), 1395; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031395 - 30 Jan 2021
Cited by 6 | Viewed by 2230
Abstract
Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of [...] Read more.
Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signaling pathways activated by cyclophosphamide in mouse ovaries. We also provide evidence that Asciminib does not interfere with the cytotoxic effect of cyclophosphamide in Michigan Cancer Foundation (MCF)7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide. Taken together, these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effects of cancer therapies. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 2.0)
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20 pages, 2011 KiB  
Article
ITGA6+ Human Testicular Cell Populations Acquire a Mesenchymal Rather than Germ Cell Transcriptional Signature during Long-Term Culture
by Robert B. Struijk, Callista L. Mulder, Saskia K. M. van Daalen, Cindy M. de Winter-Korver, Aldo Jongejan, Sjoerd Repping and Ans M. M. van Pelt
Int. J. Mol. Sci. 2020, 21(21), 8269; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218269 - 04 Nov 2020
Cited by 3 | Viewed by 1938
Abstract
Autologous spermatogonial stem cell transplantation is an experimental technique aimed at restoring fertility in infertile men. Although effective in animal models, in vitro propagation of human spermatogonia prior to transplantation has proven to be difficult. A major limiting factor is endogenous somatic testicular [...] Read more.
Autologous spermatogonial stem cell transplantation is an experimental technique aimed at restoring fertility in infertile men. Although effective in animal models, in vitro propagation of human spermatogonia prior to transplantation has proven to be difficult. A major limiting factor is endogenous somatic testicular cell overgrowth during long-term culture. This makes the culture both inefficient and necessitates highly specific cell sorting strategies in order to enrich cultured germ cell fractions prior to transplantation. Here, we employed RNA-Seq to determine cell type composition in sorted integrin alpha-6 (ITGA6+) primary human testicular cells (n = 4 donors) cultured for up to two months, using differential gene expression and cell deconvolution analyses. Our data and analyses reveal that long-term cultured ITGA6+ testicular cells are composed mainly of cells expressing markers of peritubular myoid cells, (progenitor) Leydig cells, fibroblasts and mesenchymal stromal cells and only a limited percentage of spermatogonial cells as compared to their uncultured counterparts. These findings provide valuable insights into the cell type composition of cultured human ITGA6+ testicular cells during in vitro propagation and may serve as a basis for optimizing future cell sorting strategies as well as optimizing the current human testicular cell culture system for clinical use. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 2.0)
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14 pages, 2752 KiB  
Article
Interleukin-34, a Novel Paracrine/Autocrine Factor in Mouse Testis, and Its Possible Role in the Development of Spermatogonial Cells In Vitro
by Alaa Sawaied, Eitan Lunenfeld and Mahmoud Huleihel
Int. J. Mol. Sci. 2020, 21(21), 8143; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218143 - 30 Oct 2020
Cited by 7 | Viewed by 2037
Abstract
Spermatogenesis is the process of spermatogonial stem cell (SSC) proliferation and differentiation to generate sperm. This process is regulated by cell–cell interactions between Sertoli cells and developing SSCs by autocrine/paracrine and endocrine factors. It is also affected by cells in the interstitial compartment, [...] Read more.
Spermatogenesis is the process of spermatogonial stem cell (SSC) proliferation and differentiation to generate sperm. This process is regulated by cell–cell interactions between Sertoli cells and developing SSCs by autocrine/paracrine and endocrine factors. It is also affected by cells in the interstitial compartment, such as Leydig cells and peritubular cells. Here, we demonstrate, for the first time, the presence of interleukin-34 (IL-34) in Leydig, Sertoli, and peritubular cells and in the premeiotic, meiotic, and postmeiotic cells. Its receptor, colony-stimulating factor-1 (CSF-1), has already been demonstrated in Leydig, Sertoli, premeiotic, and meiotic cells. IL-34 was detected in testicular homogenates and Sertoli cell-conditioned media, and was affected by mouse age. We showed that the addition of IL-34 in vitro to isolated cells from the seminiferous tubules of 7-day-old mice, using the methylcellulose culture system (MCS), increased the percentages and expression of the premeiotic cells (VASA), the meiotic cells (BOULE), and the meiotic/postmeiotic cells (ACROSIN) after four weeks of culture, when examined by immunofluorescence staining (IF) and qPCR analysis. It is possible to suggest that IL-34 is a novel paracrine/autocrine factor involved in the development of spermatogenesis. This factor may be used in future therapeutic strategies for the treatment of male infertility. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 2.0)
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17 pages, 2634 KiB  
Article
Novel Insights on the Corpus Luteum Function: Role of Vaspin on Porcine Luteal Cell Angiogenesis, Proliferation and Apoptosis by Activation of GRP78 Receptor and MAP3/1 Kinase Pathways
by Patrycja Kurowska, Ewa Mlyczyńska, Joelle Dupont and Agnieszka Rak
Int. J. Mol. Sci. 2020, 21(18), 6823; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186823 - 17 Sep 2020
Cited by 15 | Viewed by 2525
Abstract
Formation and limited lifespan of corpus luteum (CL) are important for proper ovarian periodicity and fertility. Failed vascularization, imbalance between proliferation and apoptosis leads to luteal phase deficiency and infertility. The aim of this study was to examine the effect of vaspin on [...] Read more.
Formation and limited lifespan of corpus luteum (CL) are important for proper ovarian periodicity and fertility. Failed vascularization, imbalance between proliferation and apoptosis leads to luteal phase deficiency and infertility. The aim of this study was to examine the effect of vaspin on angiogenesis, apoptosis and proliferation as well as the involvement of 78-kDa glucose-regulated protein receptor (GRP78) and mitogen-activated kinase (MAP3/1) in these processes. Porcine luteal cells were incubated with vaspin (0.1–10 ng/mL) for 24 h to 72 h and then mRNA and protein expression of angiogenesis: vascular endothelial growth factor (VEGFA), fibroblast growth factor 2 (FGF2), angiopoietin 1 (ANGPT1), VEGFA receptors (VEGFR1, VEGFR2), apoptosis: caspase 3, bcl-2-like protein 4 (BAX), B-cell lymphoma (BCL2), and proliferation: proliferating cells nuclear antigen (PCNA), cyclin A factors as well as secretion of VEGFA, FGF2, ANGT1 were measured by real-time polymerase chain reaction (PCR), immunoblotting and enzyme-linked immunosorbent assay (ELISA), respectively. Moreover, apoptosis was assessed by caspase activity using the Caspase-Glo 3/7 assay, while proliferation was by alamarBlue. We found that vaspin enhanced luteal cell angiogenesis, proliferation, and significantly decreased apoptosis. Additionally, using GRP78 siRNA and the pharmacological inhibitor of MAP3/1 (PD98059), we observed that the effect of vaspin was reversed to the control level in all investigated processes. Taken together, our results suggest that vaspin is a new regulator of female fertility by direct regulation of CL formation and maintenance of luteal cell function. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 2.0)
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Review

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20 pages, 924 KiB  
Review
Metabolic Requirements for Spermatogonial Stem Cell Establishment and Maintenance In Vivo and In Vitro
by Anna Laura Voigt, Shiama Thiageswaran, Nathalia de Lima e Martins Lara and Ina Dobrinski
Int. J. Mol. Sci. 2021, 22(4), 1998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041998 - 18 Feb 2021
Cited by 12 | Viewed by 3672
Abstract
The spermatogonial stem cell (SSC) is a unique adult stem cell that requires tight physiological regulation during development and adulthood. As the foundation of spermatogenesis, SSCs are a potential tool for the treatment of infertility. Understanding the factors that are necessary for lifelong [...] Read more.
The spermatogonial stem cell (SSC) is a unique adult stem cell that requires tight physiological regulation during development and adulthood. As the foundation of spermatogenesis, SSCs are a potential tool for the treatment of infertility. Understanding the factors that are necessary for lifelong maintenance of a SSC pool in vivo is essential for successful in vitro expansion and safe downstream clinical usage. This review focused on the current knowledge of prepubertal testicular development and germ cell metabolism in different species, and implications for translational medicine. The significance of metabolism for cell biology, stem cell integrity, and fate decisions is discussed in general and in the context of SSC in vivo maintenance, differentiation, and in vitro expansion. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 2.0)
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