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Cellular and Molecular Mechanisms in Reproductive System Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Reproductive Cells and Development".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 19399

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Special Issue Editors

Dr. Arnab Ghosh

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Guest Editor

Hunter Medical Research Institute, The University of Newcastle, Callaghan, Australia
Interests: cancer biology; cancer diagnosis; cancer genetics; cancer immunology; cancer stem cell; cancer therapy; cellular immunology; gynaecological cancers; gynaecological diseases; stem cell biology

Prof. Dr. Majid E Warkiani

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Co-Guest Editor

School of Biomedical Engineering, UTS, Australia, Microfluidic & Tissue Engineering Laboratory and Center for Health Technologies (CHT), Institute for Biomedical Materials & Devices (IBMD), Sydney, Australia
Interests: male reproductive system; fertility; microfluidics; stem cells; nanofluidics; organ-on-a-chip; diagnostics and therapeutics
Special Issues, Collections and Topics in MDPI journals

Dr. Sujoy K. Dhara

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Co-Guest Editor

Stem Cell Laboratory, Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
Interests: stem cells; tissue specific stem cells; pluripotent stem cells; cellular reprogramming; developmental biology; tissue differentiation; tissue engineering; disease modelling; stem cell drugs; screening of therapeutic agents

Special Issue Information

Dear Colleagues,

Reproductive system diseases encompass a wide range of diseases from benign to malignant, which disrupt the usual functioning of the male and female reproductive systems. It can significantly affect fertility, pregnancy outcomes, and overall reproductive health. Thus, exploring cellular and molecular mechanisms underlying these diseases will help to develop effective diagnostic tools, treatments, and preventive strategies.

This Special Issue aims to explore the latest advancements in research related to the cellular and molecular mechanisms involved in reproductive system diseases by inviting original research articles and review articles in this area. Topics of interest related to the reproductive system are listed below. However, relevant topics outside of these keywords are also welcome.

Male reproductive system;
Female reproductive system;
Stem cell;
Cell signalling;
Pathogenesis;
Genetic factors;
Cellular mechanisms;
Molecular mechanisms;
Hormonal regulation;
Reproductive immunology;
Adverse pregnancy outcomes;
Biomarkers;
Therapeutic targets;
Infertility;
Cancers;
Sexually transmitted infections (STIs).

Overall, this Special Issue will serve as a platform to exchange ideas, insights, discoveries, and perspectives on these diseases’ pathologies.

Dr. Arnab Ghosh
Prof. Dr. Majid E Warkiani
Dr. Sujoy K. Dhara
Guest Editors

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

male reproductive system
female reproductive system
hormonal regulation
reproductive immunology
adverse pregnancy outcomes
infertility
sexually transmitted infections (STIs)

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Published Papers (8 papers)

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Research

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16 pages, 2582 KiB

Open AccessArticle

In Vitro Exposure to the Endocrine-Disrupting Chemical Climbazole Impairs Human Sperm Motility, Hormonal Signalling, and Mitochondrial Activity

by Eugenia Annunzi, Francesca Paola Luongo, Francesca Girolamo, Rosetta Ponchia, Sofia Passaponti, Paola Piomboni and Alice Luddi

Cells 2025, 14(6), 427; https://doi.org/10.3390/cells14060427 - 13 Mar 2025

Viewed by 596

Abstract

This study explores the endocrine-disrupting effects of climbazole (CBZ), an environmental and lifestyle stressor, on male fertility. The impact of CBZ on sperm vitality, motility, and molecular pathways related to hormone receptors and apoptosis was evaluated, in non-capacitated and capacitated conditions. Gene expression of key components, including hormone receptors (ESR1, ESR2, FSHR, AR), apoptosis-related genes (BAX, BCL2), and COX4l1 (involved in mitochondrial function), was analyzed. Protein tyrosine phosphorylation, a marker of capacitation, was also examined using immunofluorescence and Western blot analysis. We demonstrated that CBZ significantly reduced sperm vitality at concentrations above 25 µM and motility at 1 and 10 µM in non-capacitated and capacitated conditions. Changes in tyrosine phosphorylation patterns were also observed. Gene expression analysis revealed an upregulation of ESR1, ESR2, FSHR, and BAX, while AR and COX4l1 expression were downregulated. These findings offer new insights into the potential endocrine-disrupting and cytotoxic effects of CBZ, highlighting its potential role in compromising male reproductive health. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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12 pages, 1610 KiB

Open AccessArticle

Molecular Markers in Embryo Non-Development: Analysis of Gene Expressions (Ki-67, hTERT, HIF-1α) in Spent Embryo Culture Medium

by Nergis Özlem Kılıç, Duygu Kütük, Çağrı Öner, Senem Aslan Öztürk, Belgin Selam and Ertuğrul Çolak

Cells 2024, 13(24), 2093; https://doi.org/10.3390/cells13242093 - 18 Dec 2024

Viewed by 818

Abstract

An embryo culture medium is a specialized set of ambient conditions, technological equipment, and nutrients that embryos require to grow properly. We aimed to investigate the Ki-67, hTERT, and HIF-1α gene expression differences between developing and non-developing embryos in spent embryo culture medium. Ki-67, hTERT, and HIF-1α gene expressions were determined from the spent embryo culture medium containing developing and non-developing embryos of 20 normoresponder patients admitted to the Bahçeci Umut IVF Center. An increase in hTERT gene expression (p < 0.05) and a decrease in HIF-1α gene expression (p < 0.001) were observed in mediums of developing compared to the non-developing embryos. No difference was observed in Ki-67 gene expression (p > 0.05). While there was a correlation between Ki-67 and HIF-1α genes in the non-growing group (r < 0.01); no correlation was observed in the developing group (r > 0.05). Both normoresponder groups will be similar in terms of proliferation rate. The low HIF-1α expression that observed high telomerase activity in embryo development maintains continuity and avoids mechanisms that result in cell death. A molecular study of the embryo development in patients with similar characteristics may help to understand the pathogenesis of the disease and establish a diagnosis and specific treatment. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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13 pages, 847 KiB

Open AccessArticle

Excess Weight Impairs Oocyte Quality, as Reflected by mtDNA and BMP-15

by Emiliya Sigal, Maya Shavit, Yuval Atzmon, Nardin Aslih, Asaf Bilgory, Daniella Estrada, Mediea Michaeli, Nechama Rotfarb, Yasmin Shibli Abu-Raya, Shilhav Meisel-Sharon and Einat Shalom-Paz

Cells 2024, 13(22), 1872; https://doi.org/10.3390/cells13221872 - 12 Nov 2024

Cited by 1 | Viewed by 1123

Abstract

This prospective, case-control study evaluated the impact of obesity on oocyte quality based on mtDNA expression in cumulus cells (CC), and on bone morphogenetic protein 15 (BMP-15) and heparan sulfate proteoglycan 2 (HSPG2) in follicular fluid (FF). It included women 18 to <40 years of age, divided according to BMI < 24.9 (Group 1, n = 28) and BMI > 25 (Group 2, n = 22). Demographics, treatment, and pregnancy outcomes were compared. The mtDNA in CC, BMP-15, HSPG2, the lipid profile, the hormonal profile, and C-reactive protein were evaluated in FF and in blood samples. The BMP-15 levels in FF and the mitochondrial DNA in CC were higher in Group 1 (38.8 ± 32.5 vs. 14.3 ± 10.8 ng/mL; p = 0.001 and 1.10 ± 0.3 vs. 0.87 ± 0.18-fold change; p = 0.016, respectively) than in Group 2. High-density lipoprotein levels in blood and FF were higher in Group 1 (62 ± 18 vs. 50 ± 12 mg/dL; p = 0.015 and 34 ± 26 vs. 20.9 ± 7.2 mg/dL; p = 0.05, respectively). Group 2 had higher blood C-reactive protein (7.1 ± 5.4 vs. 3.4 ± 4.3 mg/L; p = 0.015), FF (5.2 ± 3.8 vs. 1.5 ± 1.6 mg/L; p = 0.002) and low-density lipoprotein levels (91 ± 27 vs. 71 ± 22 mg/dL; p = 0.008) vs. Group 1. Group 1 demonstrated a trend toward a better clinical pregnancy rate (47.8% vs. 28.6%: p = 0.31) and frozen embryo transfer rate (69.2% vs. 53.8; p = 0.69). Higher BMI resulted in lower BMP-15 levels and reduced mtDNA expression, which reflect decreased oocyte quality in overweight women. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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10 pages, 910 KiB

Open AccessArticle

Effect of Paternal Body Mass Index on Cumulative Live Birth Rates: Retrospective Analysis of 3048 Embryo Transfers in Couples Using Autologous Gametes

by Laura Mossetti, Irene Hervás-Herrero, María Gil-Juliá, Ana Navarro Gomez-Lechon, Rosa María Pacheco-Rendón, Rocío Rivera-Egea and Nicolás Garrido-Puchalt

Cells 2024, 13(22), 1836; https://doi.org/10.3390/cells13221836 - 6 Nov 2024

Viewed by 973

Abstract

Obesity is a multifactorial disease present worldwide and correlated with hormonal alterations that may cause a decrease in reproductive outcomes and seminal quality. However, the specific mechanisms involved are unknown. This led us to examine the relationship between paternal body mass index (BMI) and clinical reproductive outcomes by evaluating the cumulative live birth rates (CLBRs) per number of embryo transfers (ETs), embryos replaced (EmbRs), and oocytes used (OUs) in consecutive treatments until achieving the first newborn. A retrospective study was performed, and Kaplan–Meier survival curves were created to observe CLBRs with regard to the paternal BMI, adjusted by relevant confounders through Cox regression models. The participants were couples undergoing intracytoplasmic sperm injection (ICSI) and ET in Spanish IVIRMA clinics using autologous gametes. The cohort was subdivided based on paternal BMI: normal (18.5–24.99 kg/m²) (N), overweight (25–29.99 kg/m²) (OV), or obese (≥30 kg/m²) (OB) patients. A total of 4750 ICSI cycles were included, encompassing 49,485 mature oocytes, 23,963 blastocysts, and 3048 ETs. When calculating CLBRs based on the number of ETs carried out until live birth was achieved, no statistically significant differences were found (p = 0.72). After adjusting for maternal age and BMI, female infertility diagnosis, the use of preimplantation genetic testing, and the number of ETs, Cox regression showed that there were no statistically significant differences between the BMI groups (HR: 0.94 [95% CI: 0.7–1.2]; p = 0.59). When calculating CLBRs considering EmbRs, there was a similarity between the BMI groups (p = 0.57). However, there were no statistically significant differences in the adjusted Cox regression (HR: 0.93 [95% CI: 0.7–1.2]; p = 0.51). Finally, when calculating CLBRs considering OUs, the results were comparable among BMI subgroups (p = 0.75), and there were no statistically significant differences with adjusted Cox regression (HR: 0.95 [95% CI: 0.8–1.2]; p = 0.66). In conclusion, paternal BMI was not associated with clinical reproductive outcomes when considering the ETs, EmbRs, or OUs needed to reach the first liveborn (LB). Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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13 pages, 565 KiB

Open AccessArticle

A Virome and Proteomic Analysis of Placental Microbiota in Pregnancies with and without Fetal Growth Restriction

by Aleksandra Stupak, Maciej Kwiatek, Tomasz Gęca, Anna Kwaśniewska, Radosław Mlak, Robert Nawrot, Anna Goździcka-Józefiak and Wojciech Kwaśniewski

Cells 2024, 13(21), 1753; https://doi.org/10.3390/cells13211753 - 23 Oct 2024

Cited by 1 | Viewed by 1520

Abstract

Introduction: Metagenomic research has allowed the identification of numerous viruses present in the human body. Viruses may significantly increase the likelihood of developing intrauterine fetal growth restriction (FGR). The goal of this study was to examine and compare the virome of normal and FGR placentas using proteomic techniques. Methods: The study group of 18 women with late FGR was compared with 18 control patients with physiological pregnancy and eutrophic fetus. Proteins from the collected afterbirth placentas were isolated and examined using liquid chromatography linked to a mass spectrometer. Results: In this study, a group of 107 viral proteins were detected compared to 346 in the controls. In total, 41 proteins were common in both groups. In total, 64 proteins occurred only in the study group and indicated the presence of bacterial phages: E. coli, Bacillus, Mediterranenean, Edwardsiella, Propionibacterium, Salmonella, Paenibaciilus and amoebae Mimiviridae, Acanthamoeba polyphaga, Mimivivirus, Pandoravirdae, Miroviridae, Pepper plant virus golden mosaic virus, pol proteins of HIV-1 virus, and proteins of Pandoravirdae, Microviridae, and heat shock proteins of the virus Faustoviridae. Out of 297 proteins found only in the control group, only 2 viral proteins occurred statistically significantly more frequently: 1/hypothetical protein [uncultured Mediterranean phage uvMED] and VP4 [Gokushovirus WZ-2015a]. Discussion: The detection of certain viral proteins exclusively in the control group suggests that they may play a protective role. Likewise, the proteins identified only in the study group could indicate a potentially pathogenic function. A virome study may be used to identify an early infection, evaluate its progress, and possible association with fetal growth restriction. Utilizing this technology, an individualized patient therapy is forthcoming, e.g., vaccines. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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12 pages, 3508 KiB

Open AccessFeature PaperArticle

Unveiling the Differentiation Potential of Ovarian Theca Interna Cells from Multipotent Stem Cell-like Cells

by Hanne Vlieghe, Maria João Sousa, Dania Charif and Christiani A. Amorim

Cells 2024, 13(15), 1248; https://doi.org/10.3390/cells13151248 - 25 Jul 2024

Cited by 1 | Viewed by 2087

Abstract

Research question: Theca interna cells (TICs) are an indispensable cell source for ovarian follicle development and steroidogenesis. Recent studies have identified theca stem cells (TSCs) in both humans and animals. Interestingly, TSCs express mesenchymal stem cell (MSC)-related markers and can differentiate into mesenchymal lineages. MSCs are promising for tissue engineering and regenerative medicine due to their self-renewal and differentiation abilities. Therefore, this study investigated the potential origin of TICs from MSCs. Design: Whole ovaries from postmenopausal organ donors were obtained, and their cortex was cryopreserved prior to the isolation of stromal cells. These isolated cells were differentiated in vitro to TICs using cell media enriched with various growth factors and hormones. Immunocytochemistry, an enzyme-linked immunosorbent assay, flow cytometry, and reverse transcription–quantitative polymerase chain were employed at different timepoints. Data were analyzed using one-way ANOVA. Results: Immunocytochemistry showed an increase in TIC markers from day 0 to day 8 and a significant rise in MSC-like markers on day 2. This corresponds with rising androstenedione levels from day 2 to day 13. Flow cytometry identified a decreasing MSC-like cell population from day 2 onwards. The CD13+ cell population and its gene expression increased significantly over time. NGFR and PDGFRA expression was induced on days 0 and 2, respectively, compared to day 13. Conclusions: This study offers insights into MSC-like cells as the potential origin of TICs. Differentiating TICs from these widely accessible MSCs holds potential significance for toxicity studies and investigating TIC-related disorders like polycystic ovary syndrome (PCOS). Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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22 pages, 1160 KiB

Open AccessReview

Crosstalk Between Oxidative Stress and Epigenetics: Unveiling New Biomarkers in Human Infertility

by Sulagna Dutta, Pallav Sengupta, Filomena Mottola, Sandipan Das, Arif Hussain, Ahmed Ashour, Lucia Rocco, Kadirvel Govindasamy, Israel Maldonado Rosas and Shubhadeep Roychoudhury

Cells 2024, 13(22), 1846; https://doi.org/10.3390/cells13221846 - 7 Nov 2024

Cited by 5 | Viewed by 2710

Abstract

The correlation between epigenetic alterations and the pathophysiology of human infertility is progressively being elucidated with the discovery of an increasing number of target genes that exhibit altered expression patterns linked to reproductive abnormalities. Several genes and molecules are emerging as important for the future management of human infertility. In men, microRNAs (miRNAs) like miR-34c, miR-34b, and miR-122 regulate apoptosis, sperm production, and germ cell survival, while other factors, such as miR-449 and sirtuin 1 (SIRT1), influence testicular health, oxidative stress, and mitochondrial function. In women, miR-100-5p, miR-483-5p, and miR-486-5p are linked to ovarian reserve, PCOS, and conditions like endometriosis. Mechanisms such as DNA methylation, histone modification, chromatin restructuring, and the influence of these non-coding RNA (ncRNA) molecules have been identified as potential perturbators of normal spermatogenesis and oogenesis processes. In fact, alteration of these key regulators of epigenetic processes can lead to reproductive disorders such as defective spermatogenesis, failure of oocyte maturation and embryonic development alteration. One of the primary factors contributing to changes in the key epigenetic regulators appear to be oxidative stress, which arises from environmental exposure to toxic substances or unhealthy lifestyle choices. This evidence-based study, retracing the major epigenetic processes, aims to identify and discuss the main epigenetic biomarkers of male and female fertility associated with an oxidative imbalance, providing future perspectives in the diagnosis and management of infertile couples. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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31 pages, 1770 KiB

Open AccessReview

Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

by Qiwei Yang, Obianuju Sandra Madueke-Laveaux, Han Cun, Marta Wlodarczyk, Natalia Garcia, Katia Candido Carvalho and Ayman Al-Hendy

Cells 2024, 13(13), 1106; https://doi.org/10.3390/cells13131106 - 26 Jun 2024

Cited by 5 | Viewed by 8160

Abstract

Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. They have a poor prognosis with high rates of recurrence and metastasis. The five-year survival for uLMS patients is between 25 and 76%, with survival rates approaching 10–15% for patients with metastatic disease at the initial diagnosis. Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. Notably, drugs that block abnormal functions of these pathways remarkably improve survival in uLMS patients. However, due to chemotherapy resistance, there remains a need for novel drugs that can target these pathways effectively. In this review article, we provide an overview of the recent progress in ascertaining the biological functions and regulatory mechanisms in uLMS from the perspective of aberrant biological pathways, including DNA repair, immune checkpoint blockade, protein kinase and intracellular signaling pathways, and the hedgehog pathway. We review the emerging role of epigenetics and epitranscriptome in the pathogenesis of uLMS. In addition, we discuss serum markers, artificial intelligence (AI) combined with machine learning, shear wave elastography, current management and medical treatment options, and ongoing clinical trials for patients with uLMS. Comprehensive, integrated, and deeper insights into the pathobiology and underlying molecular mechanisms of uLMS will help develop novel strategies to treat patients with this aggressive tumor. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)

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