Special Issue "Male Reproductive Health and Infertility: A Look Towards the Future"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Organelle Function".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 8062

Special Issue Editors

Dr. Alice Luddi
E-Mail Website
Guest Editor
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
Interests: male infertility; spermatogenesis; female infertility; endometrial receptivity; gene expression
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Paola Piomboni
E-Mail Website
Guest Editor
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
Interests: male infertility; spermatogenesis; female infertility; endometrial receptivity; gene expression
Special Issues, Collections and Topics in MDPI journals
Dr. Rosanna Chianese
E-Mail Website
Guest Editor
Department of Experimental Medicine, University of Campania Luigi Vanvitelli, via Costantinopoli 16, 80138 Naples, Italy

Special Issue Information

Dear Colleagues,

The testicular milieu harboring germ cell progression is coordinated by gonadotropins, steroid hormones, and a complex network of autocrine and paracrine factors. The final goal of spermatogenesis is the production of highly specialized cells, the spermatozoa, essential for species continuation. Furthermore, morphological, molecular, and epigenetic quality of sperm cells is a crucial aspect to guarantee successful fertilization and a regular embryo development. Nuclear remodeling during spermatogenesis is also critical for sperm quality, since it influences acrosome biogenesis, flagellum formation, and chromosome distribution.

Paternal health at the time of conception is increasingly considered a key factor affecting offspring health. Meanwhile, paternal lifestyle, including exposure to endocrine disruptors and nutrition, can alter the phenotype of future generations, especially by remodeling the epigenetic blueprint of sperm. Following the substantial decline of sperm quality in recent decades and the strong correlation between male infertility and comorbidities such as oncologic, metabolic, cardiovascular, and autoimmune diseases, the need is clear to adequately study this alarming global health issue.

The purpose of this Special Issue is to provide a global overview of male fertility ranging from the molecular mechanisms driving a normal spermatogenesis to the molecular remodeling of sperm during epididymal transit, with a special focus on cell communication mediated by free or exosome-embedded molecules. This Special Issue focuses on innovative technological strategies, including testicular organ culture systems and emerging pluripotent stem cell technology that are expected to provide in vitro spermatogenesis in the future.

Moreover, this Issue will also cover the molecular, genetic/epigenetic, and endocrine aspects that may provide new, interesting clues in male infertility. Another important aspect will be the identification of new effective biomarkers for an early and reliable diagnosis of male infertility that may make possible the specific pharmacological management of patients.

Prof. Dr. Paola Piomboni
Dr. Alice Luddi
Dr. Rosanna Chianese
Guest Editors

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Keywords

  • sperm
  • male infertility
  • spermatogenesis
  • epigenetics
  • fertilization
  • exosomes
  • cell communication
  • oxidative stress
  • biomarkers

Published Papers (8 papers)

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Research

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Article
Seminal-Plasma-Mediated Effects on Sperm Performance in Humans
Cells 2022, 11(14), 2147; https://doi.org/10.3390/cells11142147 - 08 Jul 2022
Viewed by 325
Abstract
Seminal plasma (SP) plays a crucial role in reproduction and contains a large number of proteins, many of which may potentially modify sperm functionality. To evaluate the effects of SP identity and its protein composition on human sperm function, we treated the sperm [...] Read more.
Seminal plasma (SP) plays a crucial role in reproduction and contains a large number of proteins, many of which may potentially modify sperm functionality. To evaluate the effects of SP identity and its protein composition on human sperm function, we treated the sperm of several males with either their own or multiple foreign SPs in all possible sperm–SP combinations (full-factorial design). Then we recorded sperm motility and viability in these combinations and investigated whether the sperm performance is dependent on sperm and SP identity (or their interaction). Finally, we studied whether the above-mentioned sperm traits are affected by the abundance of three SP proteins, dipeptidyl peptidase-4 (DPP4), neutral endopeptidase (NEP), and aminopeptidase N (APN). The identity of the SP donor affected sperm swimming velocity, viability, and the proportion of hyperactivated sperm, but males’ own SP was not consistently more beneficial for sperm than foreign SPs. Furthermore, we show that sperm performance is also partly affected by the interaction between sperm and SP donor. Finally, we found that DPP4 and NEP levels in SP were positively associated with sperm swimming velocity and hyperactivation. Taken together, our results highlight the importance of seminal plasma as a potential source of biomarkers for diagnostics and therapeutic interventions for male-derived infertility. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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Article
Effect of Sperm Selection by Magnetic-Activated Cell Sorting in D-IUI: A Randomized Control Trial
Cells 2022, 11(11), 1794; https://doi.org/10.3390/cells11111794 - 30 May 2022
Viewed by 432
Abstract
Clinical outcome in assisted reproduction techniques (ARTs) is mainly influenced by the quality of gametes used. It is known that a high percentage of sperm DNA fragmentation (DNAf) decreases the success of ART clinical results. Therefore, techniques such as magnetic-activated cell sorting (MACS) [...] Read more.
Clinical outcome in assisted reproduction techniques (ARTs) is mainly influenced by the quality of gametes used. It is known that a high percentage of sperm DNA fragmentation (DNAf) decreases the success of ART clinical results. Therefore, techniques such as magnetic-activated cell sorting (MACS) help to improve results in cases of patients with a high percentage of DNAf. Cryopreservation of sperm in donor intrauterine insemination (D-IUI) treatments increases sperm DNAf, so patients using these sperm samples can benefit from using this technique. This prospective randomized national multicenter study analyzed clinical outcomes of 181 D-IUI treatments. MACS was performed after density gradient centrifugation (DGC) in 90 thawed semen donor samples (MACSG), whereas only DGC was performed in 91 thawed semen donor samples (CG). To our knowledge, this is the first study analyzing the effect of MACS on D-IUI cycles. Our results show no significant differences in gestation, live birth, or miscarriage rates between the two groups. We believe that further studies with a larger sample size are needed to evaluate the application of MACS in combination with standard IUI donor sperm preparations in fertility clinics. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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Article
Human Sperm Morphology as a Marker of Its Nuclear Quality and Epigenetic Pattern
Cells 2022, 11(11), 1788; https://doi.org/10.3390/cells11111788 - 30 May 2022
Viewed by 542
Abstract
Background: Human sperm chromatin condensation is a sum of epigenetic events that allows for the near-complete replacement of histones with protamines. Under high-magnification microscopy, nuclear vacuoles have been described as thumbprints with poor chromatin condensation. The objective of this study is to examine [...] Read more.
Background: Human sperm chromatin condensation is a sum of epigenetic events that allows for the near-complete replacement of histones with protamines. Under high-magnification microscopy, nuclear vacuoles have been described as thumbprints with poor chromatin condensation. The objective of this study is to examine whether vacuolated spermatozoa carry specific epigenetic marks, which may influence embryo development. Methods: The presence and three-dimensional distribution of ten epigenetic marks (protamine-P2, histone-H3, H3K4me1/me2/me3, H3K9me1/me2/me3, H3K27me3, H4k20me2) were evaluated and compared in morphometrically normal spermatozoa according to the presence or absence of a large vacuole occupying more than 15% of the head surface (n = 4193). Results: Vacuolated spermatozoa were significantly more frequently labelled with H3 and H3K4me3 than normal spermatozoa (88.1% ± 2.7 and 78.5% ± 5.2 vs. 74.8% ± 4.8 and 49.1% ± 7.4, respectively; p = 0.009 and p < 0.001) and significantly less marked by P2 and H3K27me3 (50.2% ± 6.2 and 63.9% ± 6.3 vs. 82.1% ± 4.4 and 73.6% ± 5.1, respectively; p < 0.001 and p = 0.028). In three dimensions, vacuoles are nuclear concavities filled with DNA carrying the H3K4me3 marker. Conclusion: High-magnification microscopy is a simple tool to estimate in real time the sperm epigenetic profile. The selection of normal spermatozoa without vacuoles and the deselection of spermatozoa with vacuoles appear to be epigenetically favorable to embryo development and safe offspring. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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Article
Deletion of Hnrnpk Gene Causes Infertility in Male Mice by Disrupting Spermatogenesis
Cells 2022, 11(8), 1277; https://doi.org/10.3390/cells11081277 - 09 Apr 2022
Viewed by 816
Abstract
HnRNPK is a heterogeneous nuclear ribonucleoprotein (hnRNP) that has been firmly implicated in transcriptional and post-transcriptional regulation. However, the molecular mechanisms by which hnRNPK orchestrates transcriptional or post-transcriptional regulation are not well understood due to early embryonic lethality in homozygous knockout mice, especially [...] Read more.
HnRNPK is a heterogeneous nuclear ribonucleoprotein (hnRNP) that has been firmly implicated in transcriptional and post-transcriptional regulation. However, the molecular mechanisms by which hnRNPK orchestrates transcriptional or post-transcriptional regulation are not well understood due to early embryonic lethality in homozygous knockout mice, especially in a tissue-specific context. Strikingly, in this study, we demonstrated that hnRNPK is strongly expressed in the mouse testis and mainly localizes to the nucleus in spermatogonia, spermatocytes, and round spermatids, suggesting an important role for hnRNPK in spermatogenesis. Using a male germ cell-specific hnRNPK-depleted mouse model, we found that it is critical for testicular development and male fertility. The initiation of meiosis of following spermatogenesis was not affected in Hnrnpk cKO mice, while most germ cells were arrested at the pachytene stage of the meiosis and no mature sperm were detected in epididymides. The further RNA-seq analysis of Hnrnpk cKO mice testis revealed that the deletion of hnRNPK disturbed the expression of genes involved in male reproductive development, among which the meiosis genes were significantly affected, and Hnrnpk cKO spermatocytes failed to complete the meiotic prophase. Together, these results identify hnRNPK as an essential regulator of spermatogenesis and male fertility. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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Article
CRISP2, CATSPER1 and PATE1 Expression in Human Asthenozoospermic Semen
Cells 2021, 10(8), 1956; https://doi.org/10.3390/cells10081956 - 31 Jul 2021
Cited by 2 | Viewed by 834
Abstract
The etiology of human asthenozoospermia is multifactorial. The need to unveil molecular mechanisms underlying this state of infertility is, thus, impelling. Circular RNAs (circRNAs) are involved in microRNA (miRNA) inhibition by a sponge activity to protect mRNA targets. All together they form the [...] Read more.
The etiology of human asthenozoospermia is multifactorial. The need to unveil molecular mechanisms underlying this state of infertility is, thus, impelling. Circular RNAs (circRNAs) are involved in microRNA (miRNA) inhibition by a sponge activity to protect mRNA targets. All together they form the competitive endogenous RNA network (ceRNET). Recently, we have identified differentially expressed circRNAs (DE-circRNAs) in normozoospermic and asthenozoospermic patients, associated with high-quality (A-spermatozoa) and low-quality (B-spermatozoa) sperm. Here, we carried out a differential analysis of CRISP2, CATSPER1 and PATE1 mRNA expression in good quality (A-spermatozoa) and low quality (B-spermatozoa) sperm fractions collected from both normozoospermic volunteers and asthenozoospermic patients. These sperm fractions are usually separated on the basis of morphology and motility parameters by a density gradient centrifugation. B-spermatozoa showed low levels of mRNAs. Thus, we identified the possible ceRNET responsible for regulating their expression by focusing on circTRIM2, circEPS15 and circRERE. With the idea that motility perturbations could be rooted in quantitative changes of transcripts in sperm, we evaluated circRNA and mRNA modulation in A-spermatozoa and B-spermatozoa after an oral amino acid supplementation known to improve sperm motility. The profiles of CRISP2, CATSPER1 and PATE1 proteins in the same fractions of sperm well matched with the transcript levels. Our data may strengthen the role of circRNAs in asthenozoospermia and shed light on the molecular pathways linked to sperm motility regulation. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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Article
In Silico Identification of miRNA–lncRNA Interactions in Male Reproductive Disorder Associated with COVID-19 Infection
Cells 2021, 10(6), 1480; https://doi.org/10.3390/cells10061480 - 12 Jun 2021
Cited by 5 | Viewed by 1582
Abstract
Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the [...] Read more.
Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA–lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA–lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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Review

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Review
Infertility in Men: Advances towards a Comprehensive and Integrative Strategy for Precision Theranostics
Cells 2022, 11(10), 1711; https://doi.org/10.3390/cells11101711 - 22 May 2022
Viewed by 685
Abstract
Male infertility is an increasing and serious medical concern, though the mechanism remains poorly understood. Impaired male reproductive function affects approximately half of infertile couples worldwide. Multiple factors related to the environment, genetics, age, and comorbidities have been associated with impaired sperm function. [...] Read more.
Male infertility is an increasing and serious medical concern, though the mechanism remains poorly understood. Impaired male reproductive function affects approximately half of infertile couples worldwide. Multiple factors related to the environment, genetics, age, and comorbidities have been associated with impaired sperm function. Present-day clinicians rely primarily on standard semen analysis to diagnose male reproductive potential and develop treatment strategies. To address sperm quality assessment bias and enhance analysis accuracy, the World Health Organization (WHO) has recommended standardized sperm testing; however, conventional diagnostic and therapeutic options for male infertility, including physical examination and semen standard analysis, remain ineffective in relieving the associated social burden. Instead, assisted reproductive techniques are becoming the primary therapeutic approach. In the post-genomic era, multiomics technologies that deeply interrogate the genome, transcriptome, proteome, and/or the epigenome, even at single-cell level, besides the breakthroughs in robotic surgery, stem cell therapy, and big data, offer promises towards solving semen quality deterioration and male factor infertility. This review highlights the complex etiology of male infertility, especially the roles of lifestyle and environmental factors, and discusses advanced technologies/methodologies used in characterizing its pathophysiology. A comprehensive combination of these innovative approaches in a global and multi-centric setting and fulfilling the suitable ethical consent could ensure optimal reproductive and developmental outcomes. These combinatorial approaches should allow for the development of diagnostic markers, molecular stratification classes, and personalized treatment strategies. Since lifestyle choices and environmental factors influence male fertility, their integration in any comprehensive approach is required for safe, proactive, cost-effective, and noninvasive precision male infertility theranostics that are affordable, accessible, and facilitate couples realizing their procreation dream. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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Review
Sperm Selection for ICSI: Do We Have a Winner?
Cells 2021, 10(12), 3566; https://doi.org/10.3390/cells10123566 - 17 Dec 2021
Cited by 5 | Viewed by 1745
Abstract
In assisted reproductive technology (ART), the aim of sperm cells’ preparation is to select competent spermatozoa with the highest fertilization potential and in this context, the intracytoplasmic sperm injection (ICSI) represents the most applied technique for fertilization. This makes the process of identifying [...] Read more.
In assisted reproductive technology (ART), the aim of sperm cells’ preparation is to select competent spermatozoa with the highest fertilization potential and in this context, the intracytoplasmic sperm injection (ICSI) represents the most applied technique for fertilization. This makes the process of identifying the perfect spermatozoa extremely important. A number of methods have now been developed to mimic some of the natural selection processes that exist in the female reproductive tract. Although many studies have been conducted to identify the election technique, many doubts and disagreements still remain. In this review, we will discuss all the sperm cell selection techniques currently available for ICSI, starting from the most basic methodologies and continuing with those techniques suitable for sperm cells with reduced motility. Furthermore, different techniques that exploit some sperm membrane characteristics and the most advanced strategy for sperm selection based on microfluidics, will be examined. Finally, a new sperm selection method based on a micro swim-up directly on the ICSI dish will be analyzed. Eventually, advantages and disadvantages of each technique will be debated, trying to draw reasonable conclusions on their efficacy in order to establish the gold standard method. Full article
(This article belongs to the Special Issue Male Reproductive Health and Infertility: A Look Towards the Future)
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