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Molecular Basis of Fertility Preservation and Restoration 3.0
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Molecular Basis of Fertility Preservation and Restoration 3.0

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 (31 August 2022) | Viewed by 17305

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,

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 articles and comprehensive review papers 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
  • infertility
  • testis
  • ovary
  • spermatogonia
  • stem cells
  • ovarian tissue
  • in vitro maturation
  • metabolism
  • transplantation
  • miRNA
  • germ cells
  • single-cell transcriptome
  • induced pluripotent stem cells
  • organ-on-chip (OoC)
  • organoids
  • microfluidic systems
  • germ cell transplantation
  • epigenetics

Related Special Issues

Published Papers (5 papers)

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Research

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16 pages, 3189 KiB  
Article
Organotypic Culture of Testicular Tissue from Infant Boys with Cryptorchidism
by Danyang Wang, Simone Hildorf, Elissavet Ntemou, Linn Salto Mamsen, Lihua Dong, Susanne Elisabeth Pors, Jens Fedder, Erik Clasen-Linde, Dina Cortes, Jørgen Thorup and Claus Yding Andersen
Int. J. Mol. Sci. 2022, 23(14), 7975; https://doi.org/10.3390/ijms23147975 - 19 Jul 2022
Cited by 6 | Viewed by 2511
Abstract
Organotypic culture of human fetal testis has achieved fertilization-competent spermatids followed by blastocysts development. This study focuses on whether the organotypic culture of testicular tissue from infant boys with cryptorchidism could support the development of spermatogonia and somatic cells. Frozen-thawed tissues were cultured [...] Read more.
Organotypic culture of human fetal testis has achieved fertilization-competent spermatids followed by blastocysts development. This study focuses on whether the organotypic culture of testicular tissue from infant boys with cryptorchidism could support the development of spermatogonia and somatic cells. Frozen-thawed tissues were cultured in two different media, with or without retinoic acid (RA), for 60 days and evaluated by tissue morphology and immunostaining using germ and somatic cell markers. During the 60-day culture, spermatocytes stained by boule-like RNA-binding protein (BOLL) were induced in biopsies cultured with RA. Increased AR expression (p < 0.001) and decreased AMH expression (p < 0.001) in Sertoli cells indicated advancement of Sertoli cell maturity. An increased number of SOX9-positive Sertoli cells (p < 0.05) was observed, while the percentage of tubules with spermatogonia was reduced (p < 0.001). More tubules with alpha-smooth muscle actin (ACTA, peritubular myoid cells (PTMCs) marker) were observed in an RA-absent medium (p = 0.02). CYP17A1/STAR-positive Leydig cells demonstrated sustained steroidogenic function. Our culture conditions support the initiation of spermatocytes and enhanced maturation of Sertoli cells and PTMCs within infant testicular tissues. This study may be a basis for future studies focusing on maintaining and increasing the number of spermatogonia and identifying different factors and hormones, further advancing in vitro spermatogenesis. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 3.0)
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18 pages, 4564 KiB  
Article
Effect of Chemotherapy Cytarabine and Acute Myeloid Leukemia on the Development of Spermatogenesis at the Adult Age of Immature Treated Mice
by Bara’ah Khaleel, Eitan Lunenfeld, Joseph Kapelushnik and Mahmoud Huleihel
Int. J. Mol. Sci. 2022, 23(7), 4013; https://doi.org/10.3390/ijms23074013 - 04 Apr 2022
Cited by 3 | Viewed by 1937
Abstract
Acute myeloid leukemia (AML) accounts for around 20% of diagnosed childhood leukemia. Cytarabine (CYT) is involved in the AML treatment regimen. AML and CYT showed impairment in spermatogenesis in human and rodents in adulthood. We successfully developed an AML disease model in sexually [...] Read more.
Acute myeloid leukemia (AML) accounts for around 20% of diagnosed childhood leukemia. Cytarabine (CYT) is involved in the AML treatment regimen. AML and CYT showed impairment in spermatogenesis in human and rodents in adulthood. We successfully developed an AML disease model in sexually immature mice. Monocytes and granulocytes were examined in all groups: untreated control, AML alone, CYT alone and AML+CYT (in combination). There was a significant increase in the counts of monocytes and granulocytes in the AML-treated immature mice (AML) compared to the control, and AML cells were demonstrated in the blood vessels of the testes. AML alone and CYT alone impaired the development of spermatogenesis at the adult age of the AML-treated immature mice. The damage was clear in the structure/histology of their seminiferous tubules, and an increase in the apoptotic cells of the seminiferous tubules was demonstrated. Our results demonstrated a significant decrease in the meiotic/post-meiotic cells compared to the control. However, CYT alone (but not AML) significantly increased the count of spermatogonial cells (premeiotic cells) that positively stained with SALL4 and PLZF per tubule compared to the control. Furthermore, AML significantly increased the count of proliferating spermatogonial cells that positively stained with PCNA in the seminiferous tubules compared to the control, whereas CYT significantly decreased the count compared to the control. Our result showed that AML and CYT affected the microenvironment/niche of the germ cells. AML significantly decreased the levels growth factors, such as SCF, GDNF and MCSF) compared to control, whereas CYT significantly increased the levels of MCSF and GDNF compared to control. In addition, AML significantly increased the RNA expression levels of testicular IL-6 (a proinflammatory cytokine), whereas CYT significantly decreased testicular IL-6 levels compared to the control group. Furthermore, AML alone and CYT alone significantly decreased RNA expression levels of testicular IL-10 (anti-inflammatory cytokine) compared to the control group. Our results demonstrate that pediatric AML disease with or without CYT treatment impairs spermatogenesis at adult age (the impairment was more pronounced in AML+CYT) compared to control. Thus, we suggest that special care should be considered for children with AML who are treated with a CYT regimen regarding their future fertility at adult age. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 3.0)
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17 pages, 3088 KiB  
Article
Granulocyte Colony-Stimulating Factor Restored Impaired Spermatogenesis and Fertility in an AML-Chemotherapy Mice Model
by Yulia Michailov, Ali AbuMadighem, Eitan Lunenfeld, Joseph Kapelushnik and Mahmoud Huleihel
Int. J. Mol. Sci. 2021, 22(20), 11157; https://doi.org/10.3390/ijms222011157 - 15 Oct 2021
Cited by 5 | Viewed by 1952
Abstract
Leukemia and treatment of male patients with anticancer therapy (aggressive chemotherapy and/or radiotherapy) may lead to infertility or even permanent male sterility. Their mechanisms of spermatogenesis impairment and the decrease in male fertility are not yet clear. We showed that under acute myeloid [...] Read more.
Leukemia and treatment of male patients with anticancer therapy (aggressive chemotherapy and/or radiotherapy) may lead to infertility or even permanent male sterility. Their mechanisms of spermatogenesis impairment and the decrease in male fertility are not yet clear. We showed that under acute myeloid leukemia (AML) conditions, alone and in combination with cytarabine (CYT), there was significant damage in the histology of seminiferous tubules, a significant increase in apoptotic cells of the seminiferous tubules, and a reduction in spermatogonial cells (SALL and PLZF) and in meiotic (CREM) and post-meiotic (ACROSIN) cells. In addition, we showed a significant impairment in sperm parameters and fertilization rates and offspring compared to control. Our results showed a significant decrease in the expression of glial cell line-derived neurotrophic factor (GDNF), macrophage colony-stimulating factor (MCSF) and stem cell factor (SCF) under AML conditions, but not under cytarabine treatment compared to control. In addition, our results showed a significant increase in the pro-inflammatory cytokine interleukin-1 (IL-1) alpha in whole testis homogenates in all treatment groups compared to the control. Increase in IL-1 beta level was shown under AML conditions. We identified for the first time the expression of GCSF receptor (GCSFR) in sperm cells. We showed that GCSF injection in combination with AML and cytarabine (AML + CYT + GCSF) extended the survival of mice for a week (from 6.5 weeks to 7.5 weeks) compared to (AML + CYT). Injection of GCSF to all treated groups (post hoc), showed a significant impact on mice testis weight, improved testis histology, decreased apoptosis and increased expression of pre-meiotic, meiotic and post- meiotic markers, improved sperm parameters, fertility capacity and number of offspring compared to the controls (without GCSF). GCSF significantly improved the spermatogonial niche expressed by increased the expression levels of testicular GDNF, SCF and MCSF growth factors in AML-treated mice and (AML + CYT)-treated mice compared to those groups without GCSF. Furthermore, GCSF decreased the expression levels of the pro-inflammatory cytokine IL-12, but increased the expression of IL-10 in the interstitial compartment compared to the relevant groups without GCSF. Our results show for the first time the capacity of post injection of GCSF into AML- and CYT-treated mice to improve the cellular and biomolecular mechanisms that lead to improve/restore spermatogenesis and male fertility. Thus, post injection of GCSF may assist in the development of future therapeutic strategies to preserve/restore male fertility in cancer patients, specifically in AML patients under chemotherapy treatments. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 3.0)
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Review

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13 pages, 307 KiB  
Review
The Role of Noncoding RNA in the Pathophysiology and Treatment of Premature Ovarian Insufficiency
by Katarzyna Pankiewicz, Piotr Laudański and Tadeusz Issat
Int. J. Mol. Sci. 2021, 22(17), 9336; https://doi.org/10.3390/ijms22179336 - 28 Aug 2021
Cited by 14 | Viewed by 3064
Abstract
Premature ovarian insufficiency (POI) is defined as a loss of ovarian function before the age of 40 years, with a prevalence rate estimated at approximately 1%. It causes infertility and is related to serious long-term health consequences, including reduced life expectancy, increased cardiovascular [...] Read more.
Premature ovarian insufficiency (POI) is defined as a loss of ovarian function before the age of 40 years, with a prevalence rate estimated at approximately 1%. It causes infertility and is related to serious long-term health consequences, including reduced life expectancy, increased cardiovascular risk, decreased bone mineral density and neurological disorders. There is currently no effective therapy for POI that is widely available in clinical practice; therefore, the treatment of patients with POI is based on hormone replacement therapy. One of the recent advances in the understanding of the pathophysiology of POI has been the role of microRNAs (miRNAs) and other noncoding RNAs (ncRNAs) in the disease. Moreover, intensive research on human folliculogenesis and reproductive biology has led to the development of novel promising therapeutic strategies with the use of exosomal miRNAs derived from mesenchymal stem cells to restore ovarian function in POI patients. This narrative review focuses on the new studies concerning the role of ncRNAs in the pathogenesis of POI, together with their potential as biomarkers of the disease and targets for therapy. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 3.0)
18 pages, 2129 KiB  
Review
In Vitro Activation Early Follicles: From the Basic Science to the Clinical Perspectives
by Kim Cat Tuyen Vo and Kazuhiro Kawamura
Int. J. Mol. Sci. 2021, 22(7), 3785; https://doi.org/10.3390/ijms22073785 - 06 Apr 2021
Cited by 30 | Viewed by 6795
Abstract
Development of early follicles, especially the activation of primordial follicles, is strictly modulated by a network of signaling pathways. Recent advance in ovarian physiology has been allowed the development of several therapies to improve reproductive outcomes by manipulating early folliculogenesis. Among these, in [...] Read more.
Development of early follicles, especially the activation of primordial follicles, is strictly modulated by a network of signaling pathways. Recent advance in ovarian physiology has been allowed the development of several therapies to improve reproductive outcomes by manipulating early folliculogenesis. Among these, in vitro activation (IVA) has been recently developed to extend the possibility of achieving genetically related offspring for patients with premature ovarian insufficiency and ovarian dysfunction. This method was established based on basic science studies of the intraovarian signaling pathways: the phosphoinositide 3-kinase (PI3K)/Akt and the Hippo signaling pathways. These two pathways were found to play crucial roles in folliculogenesis from the primordial follicle to the early antral follicle. Following the results of rodent experiments, IVA was implemented in clinical practice. There have been multiple recorded live births and ongoing pregnancies. Further investigations are essential to confirm the efficacy and safety of IVA before used widely in clinics. This review aimed to summarize the published literature on IVA and provide future perspectives for its improvement. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 3.0)
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