1
|
Bazzano MV, Köninger A, Solano ME. Beyond defence: Immune architects of ovarian health and disease. Semin Immunopathol 2024; 46:11. [PMID: 39134914 PMCID: PMC11319434 DOI: 10.1007/s00281-024-01021-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 07/23/2024] [Indexed: 08/15/2024]
Abstract
Throughout the individual's reproductive period of life the ovary undergoes continues changes, including cyclic processes of cell death, tissue regeneration, proliferation, and vascularization. Tissue-resident leucocytes particularly macrophages, play a crucial role in shaping ovarian function and maintaining homeostasis. Macrophages crucially promote angiogenesis in the follicles and corpora lutea, thereby supporting steroidogenesis. Recent research on macrophage origins and early tissue seeding has unveiled significant insights into their role in early organogenesis, e.g. in the testis. Here, we review evidence about the prenatal ovarian seeding of leucocytes, primarily macrophages with angiogenic profiles, and its connection to gametogenesis. In the prenatal ovary, germ cells proliferate, form cysts, and undergo changes that, following waves of apoptosis, give rice to the oocytes contained in primordial follicles. These follicles constitute the ovarian reserve that lasts throughout the female's reproductive life. Simultaneously, yolk-sac-derived primitive macrophages colonizing the early ovary are gradually replaced or outnumbered by monocyte-derived fetal macrophages. However, the cues indicating how macrophage colonization and follicle assembly are related are elusive. Macrophages may contribute to organogenesis by promoting early vasculogenesis. Whether macrophages contribute to ovarian lymphangiogenesis or innervation is still unknown. Ovarian organogenesis and gametogenesis are vulnerable to prenatal insults, potentially programming dysfunction in later life, as observed in polycystic ovary syndrome. Experimental and, more sparsely, epidemiological evidence suggest that adverse stimuli during pregnancy can program defective folliculogenesis or a diminished follicle reserve in the offspring. While the ovary is highly sensitive to inflammation, the involvement of local immune responses in programming ovarian health and disease remains to be thoroughly investigated.
Collapse
Affiliation(s)
- Maria Victoria Bazzano
- Laboratory of Translational Perinatology, University of Regensburg, Biopark 1-3, D-93053, Regensburg, Germany
| | - Angela Köninger
- University Department of Obstetrics and Gynecology, Clinic St. Hedwig of The Order of St. John, University of Regensburg, Steinmetzstr. 1-3, D-93049, Regensburg, Germany
| | - Maria Emilia Solano
- Laboratory of Translational Perinatology, University of Regensburg, Biopark 1-3, D-93053, Regensburg, Germany.
| |
Collapse
|
2
|
Zhang KH, Zhang FF, Zhang ZL, Fang KF, Sun WX, Kong N, Wu M, Liu HO, Liu Y, Li Z, Cai QQ, Wang Y, Wei QW, Lin PC, Lin Y, Xu W, Xu CJ, Yuan YY, Zhao SM. Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation. Protein Cell 2024; 15:512-529. [PMID: 38167949 PMCID: PMC11214834 DOI: 10.1093/procel/pwad065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit the rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH, and ASK1-JNK pathway are targetable to alleviate PCOS.
Collapse
Affiliation(s)
- Kai-Hui Zhang
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
- Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University, Shanghai 200032, China
- Pediatric Research Institute, Children’s Hospital Affiliated to Shandong University (Jinan Children’s Hospital), Jinan 250022, China
| | - Fei-Fei Zhang
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Zhi-Ling Zhang
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
- Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University, Shanghai 200032, China
- School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Ke-Fei Fang
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Wen-Xing Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226019, China
| | - Na Kong
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Min Wu
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Hai-Ou Liu
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Yan Liu
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Zhi Li
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Qing-Qing Cai
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Yang Wang
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Quan-Wei Wei
- Department of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210014, China
| | - Peng-Cheng Lin
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining 810007, China
| | - Yan Lin
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
- Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University, Shanghai 200032, China
| | - Wei Xu
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
- Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University, Shanghai 200032, China
- Shanghai Fifth People’s Hospital of Fudan University, Fudan University, Shanghai 200240, China
| | - Cong-Jian Xu
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
| | - Yi-Yuan Yuan
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
- Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University, Shanghai 200032, China
| | - Shi-Min Zhao
- The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200090, China
- Shanghai Key Laboratory of Metabolic Remodeling, and Children’s Hospital of Fudan University, Shanghai 200032, China
- School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining 810007, China
| |
Collapse
|
3
|
Yeşil Sarsmaz H, Gürgen SG, Cansu A, Türkmen S, Gündüz A. The relationship between oxidative stress and apoptosis of histopathological changes in the ovary made by mad honey containing grayanotoxin. Food Chem Toxicol 2024; 187:114634. [PMID: 38582344 DOI: 10.1016/j.fct.2024.114634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/22/2024] [Accepted: 03/29/2024] [Indexed: 04/08/2024]
Abstract
The purpose of this study is to determine the effects of grayanotoxin in mad honey on ovarian tissue folliculogenesis in terms of cell death and nitric oxide expression. Three groups of 18 female Sprague-Dawley rats were formed. The first group received mad honey (80 mg/kg), the second group received normal honey (80 mg/kg), and the third group was the control. The first and second groups received normal and mad honey by oral gavage for 30 days before being sacrificed under anesthesia. Caspase 3 immunostaining showed a moderate to strong response, particularly in the mad honey group. In the mad honey group, immunostaining for caspase 8 and caspase 9 revealed a moderate immunoreaction in the granulosa cells of the Graaf follicles. The majority of Graaf follicles exhibited TUNEL positive in the mad honey group. The iNOS immunoreaction revealed a high level of expression in the mad honey group. In all three groups, eNOS immunostaining showed weak reactivity. According to the findings of apoptotic and nitric oxide marker expression, it was determined that mad honey may result in an increase in follicular atresia in ovarian follicles when compared to normal honey and control groups.
Collapse
Affiliation(s)
- Hayrunnisa Yeşil Sarsmaz
- Department of Histology and Embryology, Manisa Celal Bayar University Faculty of Health Sciences, Manisa, Turkey.
| | - Seren Gülşen Gürgen
- Department of Histology and Embryology, Manisa Celal Bayar University Vocational School of Health Services, Manisa, Turkey
| | - Ali Cansu
- Department of Pediatric Neurology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey
| | - Süha Türkmen
- Department of Emergency Medicine, Qatar University, Doha, Qatar
| | - Abdülkadir Gündüz
- Department of Emergency Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| |
Collapse
|
4
|
Zhang J, Qin M, Kao C, Shi Y, Yang Z, Chen T, Liu M, Fang L, Gao F, Qin Y, Ding L. PDCD4 deficiency improved 4-vinylcyclohexene dioxide-induced mouse premature ovarian insufficiency. Reprod Biomed Online 2024; 48:103685. [PMID: 38324980 DOI: 10.1016/j.rbmo.2023.103685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 10/23/2023] [Accepted: 11/01/2023] [Indexed: 02/09/2024]
Abstract
RESEARCH QUESTION What role does programmed cell death 4 (PDCD4) play in premature ovarian insufficiency (POI)? DESIGN A PDCD4 gene knockout (PDCD4-/-) mouse model was constructed, a POI mouse model was established similar to human POI with 4-vinylcyclohexene dioxide (VCD), a PDCD4-overexpressed adenovirus was designed and the regulatory role in POI in vitro and in vivo was investigated. RESULTS PDCD4 expression was significantly increased in the ovarian granulosa cells of patients with POI (P ≤ 0.002 protein and mRNA) and mice with VCD-induced POI (P < 0.001 protein expression in both mouse ovaries and granulosa cells). In POI-induced mice model, PDCD4 knockouts significantly increased anti-Müllerian hormone, oestrodiol and numbers of developing follicles, and the PI3K-AKT-Bcl2/Bax signalling pathway is involved in it. CONCLUSION The expression and regulation of PDCD4 significantly affects the POI pathology in a mouse model. This effect is closely related to the regulation of Bcl2/Bax and the activation of the PI3K-AKT signalling pathway.
Collapse
Affiliation(s)
- Jie Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Mengzhen Qin
- Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Clinical Research Center for Reproductive Health, Shandong Technology Innovation Center for Reproductive Health, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China
| | - Chunyu Kao
- Institute for Financial Studies, Shandong University, Jinan, Shandong, China
| | - Ying Shi
- Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Clinical Research Center for Reproductive Health, Shandong Technology Innovation Center for Reproductive Health, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China
| | - Zhi Yang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Tao Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Minghao Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Liang Fang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Fei Gao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yingying Qin
- Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Clinical Research Center for Reproductive Health, Shandong Technology Innovation Center for Reproductive Health, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China
| | - Lingling Ding
- Reproductive Endocrinology of Ministry of Education, Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Clinical Research Center for Reproductive Health, Shandong Technology Innovation Center for Reproductive Health, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China..
| |
Collapse
|
5
|
Anima B, Gurusubramanian G, Roy VK. Possible role of apelin on the ovarian steroidogenesis and uterine apoptosis of infantile mice: An in vitro study. J Steroid Biochem Mol Biol 2024; 238:106463. [PMID: 38246202 DOI: 10.1016/j.jsbmb.2024.106463] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/04/2024] [Accepted: 01/17/2024] [Indexed: 01/23/2024]
Abstract
The expression of adipokines is well-known in the ovary and uterus. Recently we have shown that apelin and its receptor, APJ are developmentally regulated in the ovary and uterus of mice with elevation at postnatal day 14 (PND14). However, its role in the ovary and uterus of PND14 has not been investigated. Thus, we aimed to unravel the role of the apelin system (by APJ antagonist, ML221) on ovarian steroid secretion, proliferation, and apoptosis along with its role in uterine apoptosis in PND14 mice by in vitro approaches. The treatment of ML221 decreased estrogen, testosterone, and androstenedione secretion while increasing the progesterone secretion from the infantile ovary. These results suggest that apelin signaling would be important for ovarian estrogen synthesis in infantile mice (PND14). The abundance of 3β-HSD, 17β-HSD, aromatase, and active caspase3 increased in the infantile ovary after ML221 treatment. The expression of ERs and BCL2 were also down-regulated by ML221 treatment. The decreased BCL2 and increased active caspase3 by ML221 suggest the suppressive role of apelin on ovarian apoptosis. The APJ antagonist treatment also down-regulated the ER expression in the uterus along with increased active caspase3 and decreased BCL2 expression. In conclusion, apelin signaling inhibits the ovarian and uterine apoptosis via estrogen signaling in the ovary and uterus.
Collapse
Affiliation(s)
- Borgohain Anima
- Department of Zoology, Mizoram University, Aizawl 796004, Mizoram, India
| | | | - Vikas Kumar Roy
- Department of Zoology, Mizoram University, Aizawl 796004, Mizoram, India.
| |
Collapse
|
6
|
Chesnokov MS, Mamedova AR, Zhivotovsky B, Kopeina GS. A matter of new life and cell death: programmed cell death in the mammalian ovary. J Biomed Sci 2024; 31:31. [PMID: 38509545 PMCID: PMC10956231 DOI: 10.1186/s12929-024-01017-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/27/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND The mammalian ovary is a unique organ that displays a distinctive feature of cyclic changes throughout the entire reproductive period. The estrous/menstrual cycles are associated with drastic functional and morphological rearrangements of ovarian tissue, including follicular development and degeneration, and the formation and subsequent atrophy of the corpus luteum. The flawless execution of these reiterative processes is impossible without the involvement of programmed cell death (PCD). MAIN TEXT PCD is crucial for efficient and careful clearance of excessive, depleted, or obsolete ovarian structures for ovarian cycling. Moreover, PCD facilitates selection of high-quality oocytes and formation of the ovarian reserve during embryonic and juvenile development. Disruption of PCD regulation can heavily impact the ovarian functions and is associated with various pathologies, from a moderate decrease in fertility to severe hormonal disturbance, complete loss of reproductive function, and tumorigenesis. This comprehensive review aims to provide updated information on the role of PCD in various processes occurring in normal and pathologic ovaries. Three major events of PCD in the ovary-progenitor germ cell depletion, follicular atresia, and corpus luteum degradation-are described, alongside the detailed information on molecular regulation of these processes, highlighting the contribution of apoptosis, autophagy, necroptosis, and ferroptosis. Ultimately, the current knowledge of PCD aberrations associated with pathologies, such as polycystic ovarian syndrome, premature ovarian insufficiency, and tumors of ovarian origin, is outlined. CONCLUSION PCD is an essential element in ovarian development, functions and pathologies. A thorough understanding of molecular mechanisms regulating PCD events is required for future advances in the diagnosis and management of various disorders of the ovary and the female reproductive system in general.
Collapse
Affiliation(s)
- Mikhail S Chesnokov
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
| | - Aygun R Mamedova
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Boris Zhivotovsky
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia.
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
| | - Gelina S Kopeina
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia.
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
| |
Collapse
|
7
|
Bakhshalizadeh S, Bird AD, Sreenivasan R, Bell KM, Robevska G, van den Bergen J, Asghari-Jafarabadi M, Kueh AJ, Touraine P, Lokchine A, Jaillard S, Ayers KL, Wilhelm D, Sinclair AH, Tucker EJ. A Human Homozygous HELQ Missense Variant Does Not Cause Premature Ovarian Insufficiency in a Mouse Model. Genes (Basel) 2024; 15:333. [PMID: 38540391 PMCID: PMC10970702 DOI: 10.3390/genes15030333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 02/26/2024] [Accepted: 02/29/2024] [Indexed: 04/02/2024] Open
Abstract
Disruption of meiosis and DNA repair genes is associated with female fertility disorders like premature ovarian insufficiency (POI). In this study, we identified a homozygous missense variant in the HELQ gene (c.596 A>C; p.Gln199Pro) through whole exome sequencing in a POI patient, a condition associated with disrupted ovarian function and female infertility. HELQ, an enzyme involved in DNA repair, plays a crucial role in repairing DNA cross-links and has been linked to germ cell maintenance, fertility, and tumour suppression in mice. To explore the potential association of the HELQ variant with POI, we used CRISPR/Cas9 to create a knock-in mouse model harbouring the equivalent of the human HELQ variant identified in the POI patient. Surprisingly, Helq knock-in mice showed no discernible phenotype, with fertility levels, histological features, and follicle development similar to wild-type mice. Despite the lack of observable effects in mice, the potential role of HELQ in human fertility, especially in the context of POI, should not be dismissed. Larger studies encompassing diverse ethnic populations and alternative functional approaches will be necessary to further examine the role of HELQ in POI. Our results underscore the potential uncertainties associated with genomic variants and the limitations of in vivo animal modelling.
Collapse
Affiliation(s)
- Shabnam Bakhshalizadeh
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Anthony D. Bird
- Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; (A.D.B.); (D.W.)
- Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, VIC 3168, Australia
- Department of Molecular & Translational Science, Monash University, Melbourne, VIC 3168, Australia
| | - Rajini Sreenivasan
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
| | - Katrina M. Bell
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
| | - Gorjana Robevska
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
| | - Jocelyn van den Bergen
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
| | - Mohammad Asghari-Jafarabadi
- Biostatistics Unit, School of Public Health and Preventative Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC 3004, Australia;
- Department of Psychiatry, School of Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Andrew J. Kueh
- The Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia;
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
| | - Philippe Touraine
- Department of Endocrinology and Reproductive Medicine, Pitie Salpetriere Hospital, AP-HP, Sorbonne University Medicine, 75013 Paris, France;
| | - Anna Lokchine
- IRSET (Institut de Recherche en Santé, Environnement et Travail), INSERM/EHESP/Univ Rennes/CHU Rennes–UMR_S 1085, 35000 Rennes, France; (A.L.); (S.J.)
- CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, 35033 Rennes, France
| | - Sylvie Jaillard
- IRSET (Institut de Recherche en Santé, Environnement et Travail), INSERM/EHESP/Univ Rennes/CHU Rennes–UMR_S 1085, 35000 Rennes, France; (A.L.); (S.J.)
- CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, 35033 Rennes, France
| | - Katie L. Ayers
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Dagmar Wilhelm
- Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; (A.D.B.); (D.W.)
| | - Andrew H. Sinclair
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Elena J. Tucker
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; (S.B.); (R.S.); (K.M.B.); (G.R.); (J.v.d.B.); (K.L.A.); (A.H.S.)
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
| |
Collapse
|
8
|
Hu H, Zhang J, Xin X, Jin Y, Zhu Y, Zhang H, Fan R, Ye Y, Li D. Efficacy of natural products on premature ovarian failure: a systematic review and meta-analysis of preclinical studies. J Ovarian Res 2024; 17:46. [PMID: 38378652 PMCID: PMC10877904 DOI: 10.1186/s13048-024-01369-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/05/2024] [Indexed: 02/22/2024] Open
Abstract
OBJECTIVE This study aims to investigate the effects of natural products on animal models of premature ovarian failure (POF). METHODS We conducted comprehensive literature searches and identified relevant studies that examined the protective effects of natural products on experimental POF. We extracted quantitative data on various aspects such as follicular development, ovarian function, physical indicators, oxidative stress markers, inflammatory factors, and protein changes. The data was analyzed using random-effects meta-analyses, calculating pooled standardized mean differences and 95% confidence intervals. Heterogeneity was assessed using the I2 statistic, and bias was estimated using the SYRCLE tool. RESULTS Among the 879 reviewed records, 25 articles met our inclusion criteria. These findings demonstrate that treatment with different phytochemicals and marine natural products (flavonoids, phenols, peptides, and alkaloids, etc.) significantly improved various aspects of ovarian function compared to control groups. The treatment led to an increase in follicle count at different stages, elevated levels of key hormones, and a decrease in atretic follicles and hormone levels associated with POF. This therapy also reduced oxidative stress (specifically polyphenols, resveratrol) and apoptotic cell death (particularly flavonoids, chrysin) in ovarian granulosa cells, although it showed no significant impact on inflammatory responses. The certainty of evidence supporting these findings ranged from low to moderate. CONCLUSIONS Phytochemicals and marine natural product therapy (explicitly flavonoids, phenols, peptides, and alkaloids) has shown potential in enhancing folliculogenesis and improving ovarian function in animal models of POF. These findings provide promising strategies to protect ovarian reserve and reproductive health. Targeting oxidative stress and apoptosis pathways may be the underlying mechanism.
Collapse
Affiliation(s)
- Hangqi Hu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Jiacheng Zhang
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Xiyan Xin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Yuxin Jin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Yutian Zhu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Haolin Zhang
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Ruiwen Fan
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Yang Ye
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China.
| | - Dong Li
- Department of Traditional Chinese Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China.
| |
Collapse
|
9
|
Kakinuma K, Kakinuma T. Significance of oxidative stress and antioxidant capacity tests as biomarkers of premature ovarian insufficiency: A case control study. World J Clin Cases 2024; 12:479-487. [PMID: 38322464 PMCID: PMC10841946 DOI: 10.12998/wjcc.v12.i3.479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/27/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Premature ovarian insufficiency (POI) is a condition that causes secondary amenorrhea owing to ovarian hypofunction at an early stage. Early follicular depletion results in intractable infertility, thereby considerably reducing the quality of life of females. Given the continuum in weakened ovarian function, progressing from incipient ovarian failure (IOF) to transitional ovarian failure and further to POI, it is necessary to develop biomarkers for predicting POI. The oxidative stress states in IOF and POI were comprehensively evaluated via oxidative stress [diacron-reactive oxygen metabolites (d-ROMs)] test and antioxidant capacity [biological antioxidant potential (BAP)]. AIM To explore the possibilities of oxidative stress and antioxidant capacity as biomarkers for the early detection of POI. METHODS Females presenting with secondary amenorrhea over 4 mo and a follicle stimulating hormone level of > 40 mIU/mL were categorized into the POI group. Females presenting with a normal menstrual cycle and a follicle stimulating hormone level of > 10.2 mIU/mL were categorized into the IOF group. Healthy females without ovarian hypofunction were categorized into the control group. Among females aged < 40 years who visited our hospital from January 2021 to June 2022, we recruited 11 patients into both POI and IOF groups. For the potential antioxidant capacity, the relative oxidative stress index (BAP/d-ROMs × 100) was calculated, and the oxidative stress defense system was comprehensively evaluated. RESULTS d-ROMs were significantly higher in the POI and IOF groups than in the control group, (478.2 ± 58.7 U.CARR, 434.5 ± 60.6 U.CARR, and 341.1 ± 35.1 U.CARR, respectively) (U.CARR is equivalent to 0.08 mg/dL of hydrogen peroxide). However, no significant difference was found between the POI and IOF groups. Regarding BAP, no significant difference was found between the control, IOF, and POI groups (2078.5 ± 157.4 μmol/L, 2116.2 ± 240.2 μmol/L, and 2029.0 ± 186.4 μmol/L, respectively). The oxidative stress index was significantly higher in the POI and IOF groups than in the control group (23.7 ± 3.3, 20.7 ± 3.6, and 16.5 ± 2.1, respectively). However, no significant difference was found between the POI and IOF groups. CONCLUSION High levels of oxidative stress suggest that evaluating the oxidative stress state may be a useful indicator for the early detection of POI.
Collapse
Affiliation(s)
- Kaoru Kakinuma
- Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan
- Graduate School of Medicine, International University of Health and Welfare, Tokyo 107-8402, Japan
| | - Toshiyuki Kakinuma
- Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan
| |
Collapse
|
10
|
Dey P, Monferini N, Donadini L, Lodde V, Franciosi F, Luciano AM. Method of Isolation and In Vitro Culture of Primordial Follicles in Bovine Animal Model. Methods Mol Biol 2024; 2770:171-182. [PMID: 38351454 DOI: 10.1007/978-1-0716-3698-5_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
The mammalian ovary is a substantial source of oocytes arranged into follicles at various stages of folliculogenesis, from the primordial to the ovulatory ones. Primordial follicles constitute the most abundant source of gametes inside the mammalian ovary at any given time.The isolation of a high number of primordial follicles, together with the development of protocols for in vitro follicle growth, would provide a powerful tool to fully exploit the female reproductive potential and boost the rescue and restoration of fertility in assisted reproduction technologies in human medicine, animal breeding, and preservation of threatened species. However, the most significant limitation is the lack of efficient methods for isolating a healthy and homogeneous population of viable primordial follicles suitable for in vitro culture. Here, we provide a fast and high-yield strategy for the mechanical isolation of primordial follicles from limited portions of the ovarian cortex in the bovine animal model.
Collapse
Affiliation(s)
- Pritha Dey
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy
| | - Noemi Monferini
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy
| | - Ludovica Donadini
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy
| | - Valentina Lodde
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy
| | - Federica Franciosi
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy
| | - Alberto Maria Luciano
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, University of Milan, Milan, Italy.
| |
Collapse
|
11
|
Yang W, Yu S, Peng J, Chang P, Chen X. FGF12 regulates cell cycle gene expression and promotes follicular granulosa cell proliferation through ERK phosphorylation in geese. Poult Sci 2023; 102:102937. [PMID: 37494810 PMCID: PMC10394013 DOI: 10.1016/j.psj.2023.102937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/10/2023] [Accepted: 07/15/2023] [Indexed: 07/28/2023] Open
Abstract
The granulosa cells play an important role in the fate of follicular development or atresia in poultry. Fibroblast growth factor 12 (FGF12) is downregulated in atretic follicles and may be involved in regulating granulosa cell survival in previous studies, but its molecular mechanism remains unclear. In this study, FGF12 overexpression and knockdown models of goose granulosa cells were constructed to investigate its function. The downstream expression of the cell cycle pathway was analyzed by qPCR. Granulosa cell proliferative activity and apoptosis were detected by CCK8 and TUNEL. Protein phosphorylation levels of ERK and AKT were measured using Western blotting to analyze the key pathway of FGF12 regulation of granulosa cell proliferation. ERK protein phosphorylation inhibitor was added for further verification. After overexpression of FGF12, cell proliferation activity was increased, the expressions of cell cycle pathway genes CCND1, CCNA2, MAD2, and CHK1 were upregulated, the apoptosis of granulosa cell was decreased, and Caspase 3 gene and protein expression were downregulated. After the knockdown of FGF12, cell proliferation activity decreased, the expression of downstream genes in the cell cycle pathway was downregulated, the apoptosis of granulosa cells was increased, and the Bcl-2 gene and protein were downregulated. Overexpression of FGF12 promoted the synthesis of P4 and upregulates the expression of the STAR gene. Overexpression of FGF12 promoted ERK protein phosphorylation but did not affect AKT phosphorylation. The addition of ERK phosphorylation inhibitors resulted in the elimination of the increase in cell proliferative activity caused by FGF12 overexpression. In conclusion, FGF12 could promote proliferation and inhibit apoptosis of goose granulosa cells by increasing ERK phosphorylation.
Collapse
Affiliation(s)
- Wanli Yang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Shiqi Yu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Jinzhou Peng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Penghui Chang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Xingyong Chen
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China; Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, Anhui Agricultural University, Hefei 230036, China.
| |
Collapse
|
12
|
Adashev VE, Kotov AA, Olenina LV. RNA Helicase Vasa as a Multifunctional Conservative Regulator of Gametogenesis in Eukaryotes. Curr Issues Mol Biol 2023; 45:5677-5705. [PMID: 37504274 PMCID: PMC10378496 DOI: 10.3390/cimb45070358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/29/2023] Open
Abstract
Being a conservative marker of germ cells across metazoan species, DEAD box RNA helicase Vasa (DDX4) remains the subject of worldwide investigations thanks to its multiple functional manifestations. Vasa takes part in the preformation of primordial germ cells in a group of organisms and contributes to the maintenance of germline stem cells. Vasa is an essential player in the piRNA-mediated silencing of harmful genomic elements and in the translational regulation of selected mRNAs. Vasa is the top hierarchical protein of germ granules, liquid droplet organelles that compartmentalize RNA processing factors. Here, we survey current advances and problems in the understanding of the multifaceted functions of Vasa proteins in the gametogenesis of different eukaryotic organisms, from nematodes to humans.
Collapse
Affiliation(s)
- Vladimir E Adashev
- Department of Molecular Mechanisms for Realization of Genetic Information, Laboratory of Biochemical Genetics of Animals, National Research Center "Kurchatov Institute", Kurchatov Sq. 1, 123182 Moscow, Russia
| | - Alexei A Kotov
- Department of Molecular Mechanisms for Realization of Genetic Information, Laboratory of Biochemical Genetics of Animals, National Research Center "Kurchatov Institute", Kurchatov Sq. 1, 123182 Moscow, Russia
| | - Ludmila V Olenina
- Department of Molecular Mechanisms for Realization of Genetic Information, Laboratory of Biochemical Genetics of Animals, National Research Center "Kurchatov Institute", Kurchatov Sq. 1, 123182 Moscow, Russia
| |
Collapse
|
13
|
Aprison EZ, Dzitoyeva S, Ruvinsky I. Serotonergic signaling plays a deeply conserved role in improving oocyte quality. Dev Biol 2023; 499:24-30. [PMID: 37121310 PMCID: PMC10247452 DOI: 10.1016/j.ydbio.2023.04.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/02/2023]
Abstract
Declining germline quality is a major cause of reproductive senescence. Potential remedies could be found by studying regulatory pathways that promote germline quality. Several lines of evidence, including a C. elegans male pheromone ascr#10 that counteracts the effects of germline aging in hermaphrodites, suggest that the nervous system plays an important role in regulating germline quality. Inspired by the fact that serotonin mediates ascr#10 signaling, here we show that serotonin reuptake inhibitors recapitulate the effects of ascr#10 on the germline and promote healthy oocyte aging in C. elegans. Surprisingly, we found that pharmacological increase of serotonin signaling stimulates several developmental processes in D. melanogaster, including improved oocyte quality, although underlying mechanisms appear to be different between worms and flies. Our results reveal a plausibly conserved role for serotonin in maintaining germline quality and identify a class of therapeutic interventions using available compounds that could efficiently forestall reproductive aging.
Collapse
Affiliation(s)
- Erin Z Aprison
- Department of Molecular Biosciences, Northwestern University, Evanston, IL, 60208, USA
| | - Svetlana Dzitoyeva
- Department of Molecular Biosciences, Northwestern University, Evanston, IL, 60208, USA
| | - Ilya Ruvinsky
- Department of Molecular Biosciences, Northwestern University, Evanston, IL, 60208, USA.
| |
Collapse
|
14
|
Kakinuma K, Kakinuma T. Analysis of oxidative stress and antioxidative potential in premature ovarian insufficiency. World J Clin Cases 2023; 11:2684-2693. [PMID: 37214574 PMCID: PMC10198121 DOI: 10.12998/wjcc.v11.i12.2684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/20/2023] [Accepted: 03/23/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Premature ovarian insufficiency (POI) is characterized by an early decline in ovarian function, inducing secondary amenorrhea. While the cause of POI has not yet been identified, the function of mitochondria in the ovaries and the cytotoxicity associated with reactive oxygen species (ROS) have been implicated in follicle pool depletion and a decline in follicle quality. Recently developed tests have enabled easy measurement of diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). The combination of these two tests is used to comprehensively assess oxidative stress in the blood.
AIM To comprehensively assess the oxidative stress of d-ROMs and BAP in POI.
METHODS Participants were classified into two groups: A POI group of 11 women aged < 40 years examined between January 2021 and June 2022 with a history of secondary amenorrhea for at least 4 mo in our hospital and an FSH value of ≥ 40 mIU/mL; and a control group of healthy women of the same age with normal ovarian function in our hospital. Plasma d-ROMs and BAP were measured in both these groups underwent. Differences between groups were assessed using the t-test.
RESULTS The mean age and mean body mass index (BMI) were 35.8 ± 3.0 years and 20.1 ± 1.9 kg/m2 in the control group and 35.8 ± 2.7 years and 19.4 ± 2.5 kg/m2 in the POI group, respectively. The mean gravidity and parity in control and POI groups were 0.6 ± 0.7 and 0.4 ± 0.5 and 0.6 ± 0.9 and 0.3 ± 0.5, respectively. The two groups did not differ significantly in terms of mean age, BMI, gravidity, or parity. The d-ROMs level was significantly higher in the POI group than in the control group (478.2 ± 58.7 vs 341.1 ± 35.1 U.CARR; P < 0.001); however, the BAP level did not significantly differ between the two groups (2078.5 ± 157.4 vs 2029.0 ± 186.4 μmol/L). The oxidase stress index (d-ROMs/BAP × 100) was significantly higher in the POI group than in the control group (23.7 ± 3.3 vs 16.5 ± 2.1; P < 0.001).
CONCLUSION Oxidative stress was significantly greater in the POI group than in the control group, suggesting oxidative stress as a factor that can serve as a POI biomarker.
Collapse
Affiliation(s)
- Kaoru Kakinuma
- Department of Obstetrics and Gynecology, International Health and Welfare Hospital, Nasushiobara 327-2763, Japan
| | - Toshiyuki Kakinuma
- Department of Obstetrics and Gynecology, International Health and Welfare Hospital, Nasushiobara 327-2763, Japan
| |
Collapse
|
15
|
Huang J, Wu T, Li Y, Zhang Y, Yu X, Xu D, Wang H. Toxic effect window of ovarian development in female offspring mice induced by prenatal prednisone exposure with different doses and time. J Ovarian Res 2023; 16:71. [PMID: 37038227 PMCID: PMC10088227 DOI: 10.1186/s13048-023-01148-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/29/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Prednisone is one of the most used synthetic glucocorticoids during pregnancy. Epidemiological investigations suggested that prenatal prednisone therapy could affect fetal development, but systematic studies on its effects on ovarian development and the "toxic effect window" remained scarce. METHODS In this study, by simulating clinical application characteristics, Kunming mice were given prednisone by oral gavage with different doses (0.25 or 1.0 mg/kg·d) or at different time gestational days (GD) (GD0-9, GD10-18, or GD0-18). Blood and ovaries of fetal mice were collected on GD18, and the serum estradiol level and the related function indexes of ovarian granulosa cells and oocytes were detected. RESULTS Compared with the control group, prenatal prednisone exposure (PPE) induced pathological injury and enhanced cell proliferation in fetal mice ovary. Furthermore, the expression of steroid synthesis functional genes in pre-granulosa cells, the oocyte function markers, and developmentally related genes was enhanced with different doses or at different time of PPE. The Hippo signaling was activated in the fetal ovary of PPE groups. The above changes were most significant in the low or high-dose and full-term PPE groups. CONCLUSION PPE caused various cell developmental toxicity in the fetal ovary, especially in the low or high-dose, full-term exposure groups. The potential mechanism might be related to the activation of the Hippo signaling pathway.
Collapse
Affiliation(s)
- Jing Huang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Otorhinolaryngology Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Tiancheng Wu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Yating Li
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Yuanzhen Zhang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Xingjiang Yu
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Dan Xu
- Department of Pharmacy, School of Pharmaceutical Sciences, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
| | - Hui Wang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
| |
Collapse
|
16
|
Li X, Zhu Y, Zhao T, Zhang X, Qian H, Wang J, Miao X, Zhou L, Li N, Ye L. Role of COX-2/PGE2 signaling pathway in the apoptosis of rat ovarian granulosa cells induced by MEHP. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 254:114717. [PMID: 36889213 DOI: 10.1016/j.ecoenv.2023.114717] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 06/18/2023]
Abstract
OBJECTIVE MEHP, as the metabolite of DEHP, is a widely used environmental endocrine disruptor. Ovarian granulosa cells participate in maintaining the function of ovary and COX2/PGE2 pathway may regulate the function of granulosa cells. We aimed to explore how COX-2/PGE2 pathway affects cell apoptosis in ovarian granulosa cells caused by MEHP. METHODS Primary rat ovarian granulosa cells were treated with MEHP (0, 200, 250, 300 and 350 μM) for 48 h. Adenovirus was used for over-expression of COX-2 gene. The cell viability was tested with CCK8 kits. The apoptosis level was tested by flow cytometry. The levels of PGE2 were tested with ELISA kits. The expression levels of COX-2/PGE2 pathway related genes, ovulation-related genes and apoptosis-related genes, were measured with RT-qPCR and Western blot. RESULTS MEHP decreased the cell viability. After MEHP exposure, the cell apoptosis level increased. The level of PGE2 markedly decreased. The expression levels of COX-2/PGE2 pathway related genes, ovulation-related genes and anti-apoptotic genes decreased; the expression levels of pro-apoptotic genes increased. The apoptosis level was alleviated after over-expression of COX-2, and the level of PGE2 slightly increased. The expression levels of PTGER2 and PTGER4, and the levels of ovulation-related genes increased; the levels of pro-apoptotic genes decreased. CONCLUSION MEHP can cause cell apoptosis by down-regulating the levels of ovulation-related genes via COX-2/PGE2 pathway in rat ovarian granulosa cells.
Collapse
Affiliation(s)
- Xu Li
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Ying Zhu
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Tianyang Zhao
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Xueting Zhang
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Honghao Qian
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Jia Wang
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Xiaohan Miao
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Liting Zhou
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Na Li
- Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, China; Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China.
| | - Lin Ye
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China.
| |
Collapse
|
17
|
Wang D, Tang Y, Wang Z. Role of sphingolipid metabolites in the homeostasis of steroid hormones and the maintenance of testicular functions. Front Endocrinol (Lausanne) 2023; 14:1170023. [PMID: 37008929 PMCID: PMC10065405 DOI: 10.3389/fendo.2023.1170023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/07/2023] [Indexed: 03/19/2023] Open
Abstract
With the acceleration of life pace and the increase of work pressure, the problem of male infertility has become a social problem of general concern. Sphingolipids are important regulators of many cellular processes like cell differentiation and apoptosis, which are ubiquitously expressed in all mammalian cells. Various sphingolipid catabolic enzymes can generate multiple sphingolipids like sphingosine-1-phosphate and sphingomyelin. Present studies have already demonstrated the role of steroid hormones in the physiological processes of reproduction and development through hypothalamus-pituitary-gonad axis, while recent researches also found not only sphingolipids can modulate steroid hormone secretion, but also steroid hormones can control sphingolipid metabolites, indicating the role of sphingolipid metabolites in the homeostasis of steroid hormones. Furthermore, sphingolipid metabolites not only contribute to the regulation of gametogenesis, but also mediate damage-induced germ apoptosis, implying the role of sphingolipid metabolites in the maintenance of testicular functions. Together, sphingolipid metabolites are involved in impaired gonadal function and infertility in males, and further understanding of these bioactive sphingolipids will help us develop new therapeutics for male infertility in the future.
Collapse
Affiliation(s)
- Defan Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, China
| | - Yedong Tang
- Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Zhengchao Wang
- Fujian Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, China
| |
Collapse
|
18
|
Yang W, Chen X, Liu Z, Zhao Y, Chen Y, Geng Z. Integrated transcriptome and proteome revealed that the declined expression of cell cycle-related genes associated with follicular atresia in geese. BMC Genomics 2023; 24:24. [PMID: 36647001 PMCID: PMC9843891 DOI: 10.1186/s12864-022-09088-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 12/16/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Geese exhibit relatively low reproductive performance, and follicular atresia is an important factor that restricts the egg production of geese. Systematic analysis of the regulation of follicle atresia in geese through transcriptome and proteome levels could provide meaningful information on clarifying the mechanism of follicle atresia in poultry. RESULT The granulosa cell layer was loose, disintegrated and showed apoptosis in atretic follicles and remained intact in normal follicles. The hormone levels of FSH and LH were significantly decreased in the atresia follicles compared to the normal follicles (P < 0.05). A total of 954 differentially expressed genes (DEGs, 315 increased and 639 decreased) and 161 differentially expressed proteins (DEPs, 61 increased and 100 decreased) were obtained in atresia follicles compared to normal follicles, of which, 15 genes were differentially expressed in both transcriptome and proteome. The DEGs were mainly enriched in sodium transmembrane transport, plasma membrane, and transmembrane transporter activity based on the GO enrichment analysis and in the cell cycle pathway based on the KEGG enrichment analysis. The DEPs were mainly enriched in localization, lysosome, and phospholipid-binding based on the GO enrichment analysis. Candidate genes Smad2/3, Smad4, Annexin A1 (ANXA1), Stromelysin-1 (MMP3), Serine/threonine-protein kinase (CHK1), DNA replication licensing factor (MCM3), Cyclin-A2 (CCNA2), mitotic spindle assembly checkpoint protein (MAD2), Cyclin-dependent kinase 1 (CDK1), fibroblast growth factor 12 (FGF12), and G1/S-specific cyclin-D1 (CCND1) were possibly responsible for the regulation of atresia. CONCLUSION The cell cycle is an important pathway for the regulation of follicular atresia. Sodium outflow and high expression of MMP3 and MMP9 could be responsible for structural destruction and apoptosis of follicular cells.
Collapse
Affiliation(s)
- Wanli Yang
- grid.411389.60000 0004 1760 4804College of Animal Science and Technology, Anhui Agricultural University, No. 130 Changjiang West Road, Hefei, 230036 China
| | - Xingyong Chen
- grid.411389.60000 0004 1760 4804College of Animal Science and Technology, Anhui Agricultural University, No. 130 Changjiang West Road, Hefei, 230036 China ,grid.411389.60000 0004 1760 4804Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, Anhui Agricultural University, NO. 130 Changjiang West Rd, Hefei, 230036 China
| | - Zhengquan Liu
- grid.411389.60000 0004 1760 4804College of Animal Science and Technology, Anhui Agricultural University, No. 130 Changjiang West Road, Hefei, 230036 China
| | - Yutong Zhao
- grid.411389.60000 0004 1760 4804College of Animal Science and Technology, Anhui Agricultural University, No. 130 Changjiang West Road, Hefei, 230036 China
| | - Yufei Chen
- grid.411389.60000 0004 1760 4804College of Animal Science and Technology, Anhui Agricultural University, No. 130 Changjiang West Road, Hefei, 230036 China
| | - Zhaoyu Geng
- grid.411389.60000 0004 1760 4804College of Animal Science and Technology, Anhui Agricultural University, No. 130 Changjiang West Road, Hefei, 230036 China ,grid.411389.60000 0004 1760 4804Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, Anhui Agricultural University, NO. 130 Changjiang West Rd, Hefei, 230036 China
| |
Collapse
|
19
|
Cacciottola L, Camboni A, Cernogoraz A, Donnez J, Dolmans MM. Role of apoptosis and autophagy in ovarian follicle pool decline in children and women diagnosed with benign or malignant extra-ovarian conditions. Hum Reprod 2023; 38:75-88. [PMID: 36346333 DOI: 10.1093/humrep/deac237] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 09/26/2022] [Indexed: 11/09/2022] Open
Abstract
STUDY QUESTION Which biological mechanisms are responsible for physiological ovarian reserve decline owing to aging, or pathological follicle depletion triggered by inflammation or a pro-oxidant environment throughout a woman's lifetime? SUMMARY ANSWER Ovarian follicle pool size is modulated by both apoptosis and autophagy, the first responsible for its physiological decline over time and increasing in the event of prior chemotherapy in children, and the latter playing a major role in physiological ovarian follicle pool diminution before puberty. WHAT IS KNOWN ALREADY Among the different pathways of controlled cell death, apoptosis and autophagy are implicated in follicle loss. Apoptosis participates in eliminating damaged follicles, such as those impaired by chemotherapy (CHT), but its involvement in physiological age-related follicle decline is less well understood. Autophagy has proved crucial in follicle quiescence maintenance in murine models, but its contribution to human follicle pool modulation is still unclear. STUDY DESIGN, SIZE, DURATION This retrospective study included 84 patients with benign or malignant extra-ovarian conditions aged between 1 and 35 years, with ovarian tissue stored for histological analyses at the time of cryopreservation (between 2012 and 2021) at a tertiary care center. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian fragments were used for the following analyses: hematoxylin and eosin staining for follicle count and classification; cleaved caspase-3 immunostaining to identify follicle apoptosis; and microtubule-associated proteins 1A/1B light chain 3B immunolabeling to detect follicle autophagy. Transmission electron microscopy was also carried out to investigate ultrastructural features of oocytes and granulosa cells. All analyses stratified patients by age, menarchal status (premenarchal = 32; postmenarchal = 52), potentially gonadotoxic CHT before cryopreservation (n = 14), presence of endometriosis and use of hormonal treatment. MAIN RESULTS AND THE ROLE OF CHANCE Premenarchal patients had a larger follicle pool in terms of total follicle density [mean, range 4979.98 (342.2-21789) versus 918.8 (26.18-3983), P < 0.001], but higher rates of morphologically abnormal [8.52 (0-25.37)% versus 3.54 (0-17.5)%, P < 0.001] and atretic [15.8 (0‒31.85)% versus 10.6 (0-33.33)%, P < 0.01] follicles than postmenarchal subjects. Apoptosis rates did not change with increasing age [27.94 (0-93.2)% in prepubertal subjects and 29.5 (0-100)% in postpubertal subjects], but autophagic follicles were around 10 times more common in premenarchal than postmenarchal subjects [10.21 (0-62.3)% versus 1.34 (0-25)%, P < 0.001], playing a crucial role in age-related follicle decline and elimination of 'abnormal' follicles, that are rarely seen after menarche. The impact of diagnosis and previous CHT varied according to age. In premenarchal patients with previous CHT, significantly more apoptotic [40.22 (0-100)% versus 26.79 (0-87)%, P < 0.05] and fewer abnormal [3.84 (0-10-76)% versus 9.83 (0-25.37)%, P < 0.01] follicles were detected than in subjects with no CHT prior to ovarian tissue cryopreservation, suggesting a direct effect on follicle elimination, especially of those with abnormalities. In postmenarchal subjects with previous CHT, quiescent follicle rates were lower than in patients with no CHT before tissue freezing [71.57 (0-100)% versus 85.89 (50-100)%, P < 0.05], suggesting accelerated follicle activation and growth. Moreover, increased autophagic activity was observed in the event of a cancer diagnosis compared to benign conditions after puberty [26.27 (0-100)% versus 9.48 (0-29.41)%, respectively, P < 0.05]. LIMITATIONS, REASONS FOR CAUTION The impact of specific CHT protocols could not be investigated since the group of patients with previous CHT was highly heterogeneous. WIDER IMPLICATIONS OF THE FINDINGS This study yields a deeper understanding of regulation of the follicle pool decline, showing for the first time that both apoptosis and autophagy pathways are involved in physiological follicle depletion, the latter being crucial before puberty. Moreover, our data showed a different response to non-physiological damage according to age, with higher apoptosis rates only in premenarchal subjects with previous CHT, confirming that this pathway is activated by drugs known to induce DNA damage in oocytes, such as alkylating agents, but not by cancer itself. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (F.R.S.-FNRS/FRIA FC29657 awarded to L.C., CDR J.0063.20 and grant 5/4/150/5 awarded to M.M.D.), grants from the Fondation contre le Cancer (grant 2018-042 awarded to A.Ca.), the Fondazione Comunitaria del Varesotto and Provincia di Varese ('Amalia Griffini' Fellowship in Gynecology and Obstetrics awarded to A.Ce.), Fonds Spéciaux de Recherche, Fondation St Luc and donations from the Ferrero family. The authors have no competing interests to declare. TRIAL REGISTRAION NUMBER N/A.
Collapse
Affiliation(s)
- L Cacciottola
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - A Camboni
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.,Department of Anatomopathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - A Cernogoraz
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.,Department of Gynecology and Obstetrics, F. Del Ponte Hospital, University of Insubria, Varese, Italy
| | - J Donnez
- Society for Research into Infertility, Brussels, Belgium.,Professor EM, Université Catholique de Louvain, Brussels, Belgium
| | - M M Dolmans
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.,Department of Gynecology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| |
Collapse
|
20
|
Wang J, Fang J, Feng M, Li L, Ma L, Zhao X, Dai Y. Inhibition of EED activity enhances cell survival of female germline stem cell and improves the oocytes production during oogenesis in vitro. Open Biol 2023; 13:220211. [PMID: 36695089 PMCID: PMC9874982 DOI: 10.1098/rsob.220211] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Ovarian organoids, based on female germline stem cells (FGSCs), are nowadays widely applied for reproductive medicine screening and exploring the potential mechanisms during mammalian oogenesis. However, there are still key issues that urgently need to be resolved in ovarian organoid technology, one of which is to establish a culture system that effectively expands FGSCs in vitro, as well as maintaining the unipotentcy of FGSCs to differentiate into oocytes. Here, FGSCs were EED226 treated and processed for examination of proliferation and differentiation in vitro. According to the results, EED226 specifically increased FGSC survival by decreasing the enrichment of H3K27me3 on Oct4 promoter and exon, as well as enhancing OCT4 expression and inhibiting P53 and P63 expression. Notably, we also found that FGSCs with EED226 treatment differentiated into more oocytes during oogenesis in vitro, and the resultant oocytes maintained a low level of P63 versus control at early stage development. These results demonstrated that inhibition of EED activity appeared to promote the survival of FGSCs and markedly inhibited their apoptosis during in vitro differentiation. As a result of our study, we propose an effective culture strategy to culture FGSCs and obtain oocytes in vitro, which provides a new vision for oogenesis in vitro.
Collapse
Affiliation(s)
- Jiapeng Wang
- College of Life Sciences, Inner Mongolia University, Xilingol South Road No. 49, Hohhot 010020, People's Republic of China
| | - Junxian Fang
- College of Life Sciences, Inner Mongolia University, Xilingol South Road No. 49, Hohhot 010020, People's Republic of China
| | - Mingqian Feng
- College of Life Sciences, Inner Mongolia University, Xilingol South Road No. 49, Hohhot 010020, People's Republic of China
| | - Liping Li
- College of Life Sciences, Inner Mongolia University, Xilingol South Road No. 49, Hohhot 010020, People's Republic of China
| | - Lixin Ma
- College of Life Sciences, Inner Mongolia University, Xilingol South Road No. 49, Hohhot 010020, People's Republic of China
| | - Xiaorong Zhao
- College of Life Sciences, Inner Mongolia University, Xilingol South Road No. 49, Hohhot 010020, People's Republic of China
| | - Yanfeng Dai
- College of Life Sciences, Inner Mongolia University, Xilingol South Road No. 49, Hohhot 010020, People's Republic of China
| |
Collapse
|
21
|
Spradling AC, Niu W, Yin Q, Pathak M, Maurya B. Conservation of oocyte development in germline cysts from Drosophila to mouse. eLife 2022; 11:83230. [PMID: 36445738 PMCID: PMC9708067 DOI: 10.7554/elife.83230] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022] Open
Abstract
Recent studies show that pre-follicular mouse oogenesis takes place in germline cysts, highly conserved groups of oogonial cells connected by intercellular bridges that develop as nurse cells as well as an oocyte. Long studied in Drosophila and insect gametogenesis, female germline cysts acquire cytoskeletal polarity and traffic centrosomes and organelles between nurse cells and the oocyte to form the Balbiani body, a conserved marker of polarity. Mouse oocyte development and nurse cell dumping are supported by dynamic, cell-specific programs of germline gene expression. High levels of perinatal germ cell death in this species primarily result from programmed nurse cell turnover after transfer rather than defective oocyte production. The striking evolutionary conservation of early oogenesis mechanisms between distant animal groups strongly suggests that gametogenesis and early embryonic development in vertebrates and invertebrates share even more in common than currently believed.
Collapse
Affiliation(s)
- Allan C Spradling
- Carnegie Institution for Science/Howard Hughes Medical Institute, Baltimore, United States
| | - Wanbao Niu
- Carnegie Institution for Science/Howard Hughes Medical Institute, Baltimore, United States
| | - Qi Yin
- Carnegie Institution for Science/Howard Hughes Medical Institute, Baltimore, United States
| | - Madhulika Pathak
- Carnegie Institution for Science/Howard Hughes Medical Institute, Baltimore, United States
| | - Bhawana Maurya
- Carnegie Institution for Science/Howard Hughes Medical Institute, Baltimore, United States
| |
Collapse
|
22
|
The programmed death of fetal oocytes and the correlated surveillance mechanisms. REPRODUCTIVE AND DEVELOPMENTAL MEDICINE 2022. [DOI: 10.1097/rd9.0000000000000016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
|
23
|
Stolzenbach V, Woods DC, Tilly JL. Non-neutral clonal selection and its potential role in mammalian germline stem cell dysfunction with advancing age. Front Cell Dev Biol 2022; 10:942652. [PMID: 36081905 PMCID: PMC9445274 DOI: 10.3389/fcell.2022.942652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
The concept of natural selection, or "survival of the fittest", refers to an evolutionary process in nature whereby traits emerge in individuals of a population through random gene alterations that enable those individuals to better adapt to changing environmental conditions. This genetic variance allows certain members of the population to gain an advantage over others in the same population to survive and reproduce in greater numbers under new environmental pressures, with the perpetuation of those advantageous traits in future progeny. Here we present that the behavior of adult stem cells in a tissue over time can, in many respects, be viewed in the same manner as evolution, with each stem cell clone being representative of an individual within a population. As stem cells divide or are subjected to cumulative oxidative damage over the lifespan of the organism, random genetic alterations are introduced into each clone that create variance in the population. These changes may occur in parallel to, or in response to, aging-associated changes in microenvironmental cues perceived by the stem cell population. While many of these alterations will be neutral or silent in terms of affecting cell function, a small fraction of these changes will enable certain clones to respond differently to shifts in microenvironmental conditions that arise with advancing age. In some cases, the same advantageous genetic changes that support survival and expansion of certain clones over others in the population (viz. non-neutral competition) could be detrimental to the downstream function of the differentiated stem cell descendants. In the context of the germline, such a situation would be devastating to successful propagation of the species across generations. However, even within a single generation, the “evolution” of stem cell lineages in the body over time can manifest into aging-related organ dysfunction and failure, as well as lead to chronic inflammation, hyperplasia, and cancer. Increased research efforts to evaluate stem cells within a population as individual entities will improve our understanding of how organisms age and how certain diseases develop, which in turn may open new opportunities for clinical detection and management of diverse pathologies.
Collapse
|
24
|
Sánchez-Ajofrín I, Martín-Maestro A, Medina-Chávez DA, Laborda-Gomariz JÁ, Peris-Frau P, Garde JJ, Soler AJ. Melatonin rescues the development and quality of oocytes and cumulus cells after prolonged ovary preservation: An ovine in vitro model. Theriogenology 2022; 186:1-11. [DOI: 10.1016/j.theriogenology.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/27/2022] [Accepted: 04/03/2022] [Indexed: 11/25/2022]
|
25
|
Aprison EZ, Dzitoyeva S, Angeles-Albores D, Ruvinsky I. A male pheromone that improves the quality of the oogenic germline. Proc Natl Acad Sci U S A 2022; 119:e2015576119. [PMID: 35576466 PMCID: PMC9173808 DOI: 10.1073/pnas.2015576119] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 03/24/2022] [Indexed: 11/18/2022] Open
Abstract
Pheromones exchanged by conspecifics are a major class of chemical signals that can alter behavior, physiology, and development. In particular, males and females communicate with potential mating partners via sex pheromones to promote reproductive success. Physiological and developmental mechanisms by which pheromones facilitate progeny production remain largely enigmatic. Here, we describe how a Caenorhabditis elegans male pheromone, ascr#10, improves the oogenic germline. Before most signs of aging become evident, C. elegans hermaphrodites start producing lower-quality gametes characterized by abnormal morphology, increased rates of chromosomal nondisjunction, and higher penetrance of deleterious alleles. We show that exposure to the male pheromone substantially ameliorates these defects and reduces embryonic lethality. ascr#10 stimulates proliferation of germline precursor cells in adult hermaphrodites. Coupled to the greater precursor supply is increased physiological germline cell death, which is required to improve oocyte quality in older mothers. The hermaphrodite germline is sensitive to the pheromone only during a time window, comparable in duration to a larval stage, in early adulthood. During this period, prereproductive adults assess the suitability of the environment for reproduction. Our results identify developmental events that occur in the oogenic germline in response to a male pheromone. They also suggest that the opposite effects of the pheromone on gamete quality and maternal longevity arise from competition over resource allocation between soma and the germline.
Collapse
Affiliation(s)
- Erin Z. Aprison
- Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208
| | - Svetlana Dzitoyeva
- Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208
| | | | - Ilya Ruvinsky
- Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208
| |
Collapse
|
26
|
Niu W, Spradling AC. Mouse oocytes develop in cysts with the help of nurse cells. Cell 2022; 185:2576-2590.e12. [PMID: 35623357 DOI: 10.1016/j.cell.2022.05.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/07/2022] [Accepted: 05/02/2022] [Indexed: 10/18/2022]
Abstract
Mouse germline cysts, on average, develop into six oocytes supported by 24 nurse cells that transfer cytoplasm and organelles to generate a Balbiani body. We showed that between E14.5 and P5, cysts periodically activate some nurse cells to begin cytoplasmic transfer, which causes them to shrink and turnover within 2 days. Nurse cells die by a programmed cell death (PCD) pathway involving acidification, similar to Drosophila nurse cells, and only infrequently by apoptosis. Prior to initiating transfer, nurse cells co-cluster by scRNA-seq with their pro-oocyte sisters, but during their final 2 days, they cluster separately. The genes promoting oocyte development and nurse cell PCD are upregulated, whereas the genes that repress transfer, such as Tex14, and oocyte factors, such as Nobox and Lhx8, are under-expressed. The transferred nurse cell centrosomes build a cytocentrum that establishes a large microtubule aster in the primordial oocyte that organizes the Balbiani body, defining the earliest oocyte polarity.
Collapse
Affiliation(s)
- Wanbao Niu
- Howard Hughes Medical Institute Research Laboratories, Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA
| | - Allan C Spradling
- Howard Hughes Medical Institute Research Laboratories, Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA.
| |
Collapse
|
27
|
Bühler N. The making of 'old eggs': the science of reproductive ageing between fertility and anti-ageing technologies. REPRODUCTIVE BIOMEDICINE & SOCIETY ONLINE 2022; 14:169-181. [PMID: 35024473 PMCID: PMC8732751 DOI: 10.1016/j.rbms.2021.07.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 05/09/2021] [Accepted: 07/29/2021] [Indexed: 06/14/2023]
Abstract
This article proposes going back in the history of reproductive medicine to shed light on the role of assisted reproductive technology (ART) in the making of 'old eggs'. Focusing on two key technologies - egg donation and cytoplasmic transfer - both of which contributed significantly to the production of scientific knowledge about reproductive ageing, the article suggests that ART can be analysed as 'in-vivo models' playing a pivotal role in the shift from age as a demographic variable to ageing understood in biological terms. It will shed light on the role of ART in locating age in the eggs and producing a cellular understanding of fertility decline. It argues that ART not only offers new means of reconfiguring the biological clock by extending fertility, but also reconfigures the biology of reproductive ageing itself. This becomes both the target and the means for new technological interventions, imaginaries and norms, anchored in women's bodies and a more plastic biology, and thereby illuminates hitherto underexplored aspects of the encounter between the science and technology of reproduction and anti-ageing.
Collapse
|
28
|
Ovarian tissue and oocyte cryopreservation prior to iatrogenic premature ovarian insufficiency. Best Pract Res Clin Obstet Gynaecol 2021; 81:119-133. [PMID: 34887172 DOI: 10.1016/j.bpobgyn.2021.09.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/24/2021] [Accepted: 09/29/2021] [Indexed: 11/21/2022]
Abstract
Gonadotoxic treatments like chemotherapy or radiotherapy and ovarian surgery may result in an accelerated depletion of the ovarian reserve and subsequent premature ovarian insufficiency. Important determinants of this severe risk that require fertility preservation strategies are patient age, ovarian reserve, type of treatment, and administered dose. Oocytes and ovarian tissue can both be cryopreserved, with encouraging results in terms of pregnancy and live birth rates according to recent publications. Moreover, since ovarian tissue transplantation also results in long-term endocrine resumption, it represents a potential future therapeutic option for complete ovarian function restoration in patients with premature ovarian insufficiency.
Collapse
|
29
|
Odeh OM, Awwad J, Khalife D, Ghunaim S. The use of GnRH analogs in preserving ovarian function during chemotherapy. MIDDLE EAST FERTILITY SOCIETY JOURNAL 2021. [DOI: 10.1186/s43043-021-00088-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The literature has always been controversial on the use of gonadotropin-releasing hormone agonists in preserving fertility in women of childbearing age after chemotherapy; thereby, in this article, we will be discussing its use in preserving fertility.
Main body of abstract
When it comes to preserving fertility, it is crucial to consider all available options in this topic due to its very sensitive nature, thereby we have found that while a lot of trials favor the use of gonadotropin-releasing hormone agonists, the lack of proper follow-up and long-term trials renders its use highly debatable, and since the longest follow-up trial showed non-significant results, it also opens the floor for debate on whether this short-term benefit is worth adding another drug to the regimen or not.
Short conclusion
As described in this review, while the use of gonadotropin-releasing hormone agonists is beneficial in a lot of studies, the lack of long-term reports still makes its use debatable, thereby more trials should be done.
Collapse
|
30
|
Hao X, Anastácio A, Viñals-Ribé L, Santamaria Lacuesta A, Diakaki C, Alonso de Mena S, Liu K, Rodriguez-Wallberg KA. Follicle Rescue From Prepubertal Ovaries After Recent Treatment With Cyclophosphamide-An Experimental Culture System Using Mice to Achieve Mature Oocytes for Fertility Preservation. Front Oncol 2021; 11:682470. [PMID: 34631518 PMCID: PMC8497963 DOI: 10.3389/fonc.2021.682470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 09/02/2021] [Indexed: 11/13/2022] Open
Abstract
Ovarian tissue cryopreservation is the only feasible method for fertility preservation in prepubertal girls that will undergo gonadotoxic chemotherapy. To date, the only clinical use of cryopreserved tissue is by a later tissue retransplantation to the patient. Clinical challenges in fertility preservation of very young patients with cancer include time constraints that do not allow to retrieve the tissue for cryopreservation before starting chemotherapy and the preclusion of future ovarian tissue transplantation due to the risk of reintroduction of malignant cells in patients with systemic diseases. To overcome these two challenges, we investigated using an experimental model the feasibility of retrieving secondary follicles from ovaries of prepubertal mice after cyclophosphamide (CPA) treatment in increasing doses of 50, 75, and 100 mg/kg. The follicles were thereafter cultured and matured in vitro. The main outcomes included the efficiency of the method in terms of obtained matured oocytes and the safety of these potentially fertility preservative procedures in terms of analyses of oocyte competence regarding normality of the spindle and chromosome configurations. Our findings demonstrated that it was feasible to isolate and culture secondary follicles and to obtain mature oocytes from prepubertal mice ovaries recently treated with CPA. The efficiency of this method was highly demonstrated in the 100 mg/kg CPA group, with near 90% follicle survival rate after 12 days' culture, similarly to control. Around 80% of the follicles met the criteria to put into maturation, and more than 40% of them achieved metaphase II, with normal spindle and chromosome configurations observed. Suboptimal results were obtained in the 50 and 75 mg/kg CPA groups. These paradoxical findings towards CPA dose might probably reflect a more difficult selection of damaged growing follicles from ovaries recently treated with lower doses of CPA and a hampered ability to identify and discard those with reduced viability for the culture.
Collapse
Affiliation(s)
- Xia Hao
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.,Laboratory of Translational Fertility Preservation, BioClinicum, Stockholm, Sweden
| | - Amandine Anastácio
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.,Laboratory of Translational Fertility Preservation, BioClinicum, Stockholm, Sweden
| | - Laia Viñals-Ribé
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.,Laboratory of Translational Fertility Preservation, BioClinicum, Stockholm, Sweden
| | - Ana Santamaria Lacuesta
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.,Laboratory of Translational Fertility Preservation, BioClinicum, Stockholm, Sweden
| | - Christina Diakaki
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.,Laboratory of Translational Fertility Preservation, BioClinicum, Stockholm, Sweden
| | - Sara Alonso de Mena
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.,Laboratory of Translational Fertility Preservation, BioClinicum, Stockholm, Sweden
| | - Kui Liu
- Shenzhen Key Laboratory of Fertility Regulation, Center of Assisted Reproduction and Embryology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,Department of Obstetrics and Gynecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR, China
| | - Kenny A Rodriguez-Wallberg
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.,Laboratory of Translational Fertility Preservation, BioClinicum, Stockholm, Sweden.,Department of Reproductive Medicine, Division of Gynecology and Reproduction, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
31
|
Nie Z, Zhang L, Chen W, Zhang Y, Wang W, Hua R, Zhang T, Zhao C, Gong M, Wu H. The protective effects of resveratrol pretreatment in cyclophosphamide-induced rat ovarian injury: an vivo study. Gynecol Endocrinol 2021; 37:914-919. [PMID: 33594937 DOI: 10.1080/09513590.2021.1885643] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVES To explore whether resveratrol (Res) pretreatment could exert a protective effect on cyclophosphamide (Cy) induced ovarian toxicity in a rat model. METHODS Twenty-four female 7-week old Sprague-Dawley rats were randomly divided into four groups: Con, administered with vehicle solutions; Cy, treated with Cy; Res + Cy, treated with Cy + Res combined; Res, treated with Res. After 21 d of treatments, the rats were euthanized and blood samples were collected to evaluate the levels of anti-Müllerian hormone (AMH). The Ovaries were processed for immunohistochemical and western blotting. RESULTS Cy-treat caused the decrease of body weights and ovarian weight. AMH was lower in Cy group, whereas AMH levels were similar among other groups. Histomorphology showed a large number of primordial follicles were activated in Cy groups, whereas the primordial follicles were inhibited in the Res and Res + Cy groups. The expressions of Sirt1, Foxo3a were up-regulated and p53, Caspase-3, and Bax were down-regulated in Res + Cy and Res groups (p < .05). CONCLUSIONS Res can prevent the primordial follicle activation and decrease apoptosis induced by Cy. Res may be an effective protection for ovarian function during chemotherapy, which means a new nonsurgical application for protection of ovarian reserve.
Collapse
Affiliation(s)
- Zhaoyan Nie
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
- Department of Reproductive Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Lei Zhang
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Wei Chen
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Yanan Zhang
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Wei Wang
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Rui Hua
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Tiantian Zhang
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Chunfang Zhao
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Miao Gong
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, PR China
| | - Haifeng Wu
- Department of Medical Laboratory, Hebei Chest Hospital, Shijiazhuang, PR China
| |
Collapse
|
32
|
Winiarczyk D, Piliszek A, Sampino S, Lukaszewicz M, Modli Ski JA. Embryo structure reorganisation reduces the probability of apoptosis in preimplantation mouse embryos. Reprod Fertil Dev 2021; 33:725-735. [PMID: 34488937 DOI: 10.1071/rd21074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/29/2021] [Indexed: 11/23/2022] Open
Abstract
Programmed cell death plays a key role in mammalian development because the morphological events of an organism's formation are dependent on apoptosis. In the mouse development, the first apoptotic waves occur physiologically at the blastocyst stage. Cell number and the mean nucleus to cytoplasm (N/C) ratio increase exponentially throughout subsequent embryo cleavages, while cell volume concurrently decreases from the zygote to blastocyst stage. In this study we tested the hypothesis that reorganisation of the embryo structure by manipulating cell number, the N/C ratio and the cell volume of 2-cell embryos may result in the earlier and more frequent occurrence of apoptosis. The results indicate that doubling ('Aggregates' group) or halving ('Embryos 1/2' group) the initial cell number and modifying embryo volume, ploidy ('Embryos 4n' group) and the N/C ratio ('Embryos 2/1' group) reduce the probability of apoptosis in the resulting embryos. There was a higher probability of apoptosis in the inner cell mass of the blastocyst, but apoptotic cells were never observed at the morula stage in any of the experimental groups. Thus, manipulation of cell number, embryo volume, the N/C ratio and ploidy cause subtle changes in the occurrence of apoptosis, although these are mostly dependent on embryo stage and cell lineage (trophectoderm or inner cell mass), which have the greatest effect on the probability of apoptosis.
Collapse
Affiliation(s)
- Dawid Winiarczyk
- Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, Poland; and Corresponding authors. ;
| | - Anna Piliszek
- Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Silvestre Sampino
- Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Marek Lukaszewicz
- Department of Animal Improvement and Nutrigenomics, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Jacek Andrzej Modli Ski
- Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, Poland; and Corresponding authors. ;
| |
Collapse
|
33
|
van der Reest J, Nardini Cecchino G, Haigis MC, Kordowitzki P. Mitochondria: Their relevance during oocyte ageing. Ageing Res Rev 2021; 70:101378. [PMID: 34091076 DOI: 10.1016/j.arr.2021.101378] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/24/2021] [Accepted: 06/01/2021] [Indexed: 12/14/2022]
Abstract
The oocyte is recognised as the largest cell in mammalian species and other multicellular organisms. Mitochondria represent a high proportion of the cytoplasm in oocytes and mitochondrial architecture is different in oocytes than in somatic cells, characterised by a rounder appearance and fragmented network. Although the number of mitochondria per oocyte is higher than in any other mammalian cell, their number and activity decrease with advancing age. Mitochondria integrate numerous processes essential for cellular function, such as metabolic processes related to energy production, biosynthesis, and waste removal, as well as Ca2+ signalling and reactive oxygen species (ROS) homeostasis. Further, mitochondria are responsible for the cellular adaptation to different types of stressors such as oxidative stress or DNA damage. When these stressors outstrip the adaptive capacity of mitochondria to restore homeostasis, it leads to mitochondrial dysfunction. Decades of studies indicate that mitochondrial function is multifaceted, which is reflected in the oocyte, where mitochondria support numerous processes during oocyte maturation, fertilization, and early embryonic development. Dysregulation of mitochondrial processes has been consistently reported in ageing and age-related diseases. In this review, we describe the functions of mitochondria as bioenergetic powerhouses and signal transducers in oocytes, how dysfunction of mitochondrial processes contributes to reproductive ageing, and whether mitochondria could be targeted to promote oocyte rejuvenation.
Collapse
|
34
|
Colnaghi M, Pomiankowski A, Lane N. The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development. eLife 2021; 10:69344. [PMID: 34279226 PMCID: PMC8337077 DOI: 10.7554/elife.69344] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/16/2021] [Indexed: 12/16/2022] Open
Abstract
Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modeling work has not clarified the issues; here, we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.
Collapse
Affiliation(s)
- Marco Colnaghi
- CoMPLEX, University College London, London, United Kingdom.,Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
| | - Andrew Pomiankowski
- CoMPLEX, University College London, London, United Kingdom.,Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
| | - Nick Lane
- CoMPLEX, University College London, London, United Kingdom.,Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
| |
Collapse
|
35
|
Current Understandings of Core Pathways for the Activation of Mammalian Primordial Follicles. Cells 2021; 10:cells10061491. [PMID: 34199299 PMCID: PMC8231864 DOI: 10.3390/cells10061491] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
The mammalian ovary has two main functions-producing mature oocytes for fertilization and secreting hormones for maintaining the ovarian endocrine functions. Both functions are vital for female reproduction. Primordial follicles are composed of flattened pre-granulosa cells and a primary oocyte, and activation of primordial follicles is the first step in follicular development and is the key factor in determining the reproductive capacity of females. The recent identification of the phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway as the key controller for follicular activation has made the study of primordial follicle activation a hot research topic in the field of reproduction. This review systematically summarizes the roles of the PI3K/PTEN signaling pathway in primordial follicle activation and discusses how the pathway interacts with various other molecular networks to control follicular activation. Studies on the activation of primordial follicles have led to the development of methods for the in vitro activation of primordial follicles as a treatment for infertility in women with premature ovarian insufficiency or poor ovarian response, and these are also discussed along with some practical applications of our current knowledge of follicular activation.
Collapse
|
36
|
Li D, Chen J, Guo J, Li L, Cai G, Chen S, Huang J, Yang H, Zhuang Y, Wang F, Wang X. A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin 2α-induced corpus luteum regression. eLife 2021; 10:e67409. [PMID: 34029184 PMCID: PMC8143796 DOI: 10.7554/elife.67409] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/12/2021] [Indexed: 12/14/2022] Open
Abstract
Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF2α induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF2α but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knock-in mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.
Collapse
Affiliation(s)
- Dianrong Li
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - Jie Chen
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - Jia Guo
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - Lin Li
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - Gaihong Cai
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - She Chen
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - Jia Huang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesShanghaiChina
| | - Hui Yang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesShanghaiChina
| | - Yinhua Zhuang
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - Fengchao Wang
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| | - Xiaodong Wang
- National Institute of Biological SciencesBeijingChina
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua UniversityBeijingChina
| |
Collapse
|
37
|
Zhang J, Yin H, Jiang H, Du X, Yang Z. The protective effects of human umbilical cord mesenchymal stem cell-derived extracellular vesicles on cisplatin-damaged granulosa cells. Taiwan J Obstet Gynecol 2021; 59:527-533. [PMID: 32653124 DOI: 10.1016/j.tjog.2020.05.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Long term exposure to gonadotoxic chemotherapy is becoming a major cause of premature ovarian failure/insufficiency (POF/POI) with the increasing cancer incidence among young women. The present study was designed to investigate the protective effects of human cord mesenchymal stem cells (HUCMSCs)-derived extracellular vesicles (EVs) on cisplatin (CDDP)-damaged granulosa cells (GCs) in vitro. MATERIALS AND METHODS EVs were obtained from supernatant of cultured HUCMSCs by ultracentrifugation method, purified by Sucrose density gradient centrifugation, and then were co-cultured with cisplatin-damaged GCs of 3-weeks female Sprague-Dawley (SD) rats. PKH26 labeled EVs could be observed in normal and CDDP-damaged GCs after 6 h co-culture. RESULTS The surviving GCs were significantly higher and apoptotic GCs were significantly lower in EVs + CDDP group compared with CDDP group. Meanwhile, the levels of E2 and StAR (the key gene related to synthesis of steroid hormone) were significantly higher in EVs + CDDP group compared with CDDP group. Furthermore, the mRNA expression of Caspase 3 was down-regulated significantly and the ratio of Bcl-2/Bax was up-regulated significantly in EVs + CDDP group. Moreover, the protective effect of EVs on CDDP-damaged GCs showed a dose-dependent effect. CONCLUSION HUCMSCs-derived EVs could become incorporated to CDDP-damaged GCs, and increase the number of living cells, therefore playing important roles in promoting resistance to cisplatin-induced GCs apoptosis and restoring synthesis and secretion of steroid hormone in GCs. This study might provide a theoretical and experimental basis for use of mesenchymal stem cells (MSCs) derived EVs instead of MSCs as a cell-free therapeutic strategy for the patients with POI induced by chemotherapeutic agents.
Collapse
Affiliation(s)
- Jin Zhang
- Reproductive Medicine Center, The 901st Hospital, Hefei, China; Department of Obstetrics and Gynecology, Maternal and Child Health Hospital, Anhui Province, Hefei, China
| | - Huiqun Yin
- Reproductive Medicine Center, The 901st Hospital, Hefei, China
| | - Hong Jiang
- Reproductive Medicine Center, The 901st Hospital, Hefei, China.
| | - Xin Du
- Reproductive Medicine Center, The 901st Hospital, Hefei, China
| | - Ziling Yang
- Reproductive Medicine Center, The 901st Hospital, Hefei, China
| |
Collapse
|
38
|
Chen J, Todorov P, Isachenko E, Rahimi G, Mallmann P, Isachenko V. Construction and cryopreservation of an artificial ovary in cancer patients as an element of cancer therapy and a promising approach to fertility restoration. HUM FERTIL 2021; 25:651-661. [PMID: 33648431 DOI: 10.1080/14647273.2021.1885756] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The proportion of cancer patients that survive is increasing because of improvements in cancer therapy. However, some cancer treatments, such as chemo- and radio-therapies, can cause considerable damage to reproductive function. The issue of fertility is paramount for women of childbearing age once they are cured from cancer. For those patients with prepubertal or haematogenous cancer, the possibilities of conventional fertility treatments, such as oocyte or embryo cryopreservation and transplantation, are limited. Moreover, ovarian tissue cryopreservation as an alternative to fertility preservation has limitations, with a risk of re-implanting malignant cells in patients who have recovered from potentially fatal malignant disease. One possible way to restore fertility in these patients is to mimic artificially the function of the natural organ, the ovary, by grafting isolated follicles embedded in a biological scaffold to their native environment. Construction and cryopreservation of an artificial ovary might offer a safer alternative option to restore fertility for those who cannot benefit from traditional fertility preservation techniques. This review considers the protocols for constructing an artificial ovary, summarises advances in the field with potential clinical application, and discusses future trends for cryopreservation of these artificial constructions.
Collapse
Affiliation(s)
- Jing Chen
- University Maternal Hospital, Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, Cologne University, Cologne, Germany
| | - Plamen Todorov
- Institute of Biology and Immunology of Reproduction, Sofia, Bulgaria
| | - Evgenia Isachenko
- University Maternal Hospital, Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, Cologne University, Cologne, Germany
| | - Gohar Rahimi
- University Maternal Hospital, Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, Cologne University, Cologne, Germany
| | - Peter Mallmann
- University Maternal Hospital, Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, Cologne University, Cologne, Germany
| | - Vladimir Isachenko
- University Maternal Hospital, Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, Cologne University, Cologne, Germany
| |
Collapse
|
39
|
Annie L, Gurusubramanian G, Kumar Roy V. Visfatin protein may be responsible for suppression of proliferation and apoptosis in the infantile mice ovary. Cytokine 2021; 140:155422. [PMID: 33476980 DOI: 10.1016/j.cyto.2021.155422] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 11/19/2022]
Abstract
Visfatin is an important adipokines, which are expressed in different tissues including ovary of mammals. The postnatal ovary in rodents undergoes dramatic changes of intra-ovarian factors in relation to proliferation and apoptosis. There are studies which showed that gonadal visfatin changes in postnatal life. However, role of visfatin in the early postnatal period i.e. infantile period has not been studied. Therefore, the present study was aimed to explore the role of visfatin in the early postnatal ovarian functions. Furthermore, to explore the role of visfatin, the endogenous visfatin was inhibited from PND14-PND21 by FK866 with dose of 1.5 mg/kg. Our results showed gain in body weight and ovarian weight after visfatin inhibition. The inhibition of visfatin increased the ovarian proliferation (increase in PCNA, GCNA expression and BrdU incorporation) and apoptosis (increase in BAX and active caspase3 expression). Moreover, visfatin inhibition decreased the expression of antiapoptotic/survival protein, BCL2 in the ovary. These findings suggest that visfatin in the infantile ovary may suppress the proliferation and apoptosis by up-regulating BCL2 expression. An interesting finding has been observed that circulating estrogen and progesterone remain unaffected, although visfatin inhibition up-regulated ER-β and down-regulated ER-α. It may also be suggested that visfatin could regulates proliferation and apoptosis via modulating estrogen signaling. In conclusion, visfatin inhibits the proliferation and apoptosis without modulating the ovarian steroid biosynthesis and visfatin mediated BCL2 expression could also be mechanism to preserve the good quality follicle in early postnatal period.
Collapse
Affiliation(s)
| | | | - Vikas Kumar Roy
- Department of Zoology, Mizoram University, Aizawl, Mizoram - 796 004, India.
| |
Collapse
|
40
|
Lin PY, Lin CY, Tsai NC, Huang FJ, Chiang HJ, Lin YJ, Su YT, Lan KC. Disposition of embryos from women who only produced morphologically poor embryos on day three. Biomed J 2021; 45:190-199. [PMID: 35148259 PMCID: PMC9133239 DOI: 10.1016/j.bj.2021.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 11/17/2020] [Accepted: 01/11/2021] [Indexed: 11/25/2022] Open
Abstract
Background The presence of only morphologically poor embryos (MPEs) on day3 is common in autologous in vitro fertilization (IVF), particularly among p Tel: 886-7-7317123 Ext. 8916. Fax: 886-7-7322915.atients who have advanced maternal age or are poor responders. However, there are limited data regarding the disposition of embryos from patients who only produced MPEs on day3. The present study was designed to investigate the possible benefits of extended culturing MPEs. Try to detect whether the extended culture (day4 or day5 culture) can improve the live birth rate per cycle? Methods This retrospective, observational, single-center, cohort study examined 224 IVF/intracytoplasmic sperm injection (ICSI) cycles between January 2010 and June 2015, in which women only produced MPEs on day3. A total of 544 MPEs were analyzed. The defines a day3 embryo as an MPE if it fails to develop to eight cells, blastomeres of equal size, and less than 20% cytoplasmic fragments. Of the 224 cycles, 89 (39.7%) underwent fresh embryo transfer on day3, and 135 (60.3%) underwent extended culture. Of the 135 extended cultures, 54 cycles (40.0%) experienced day4, or day5 embryo transfer, 16 cycles (11.9%) had all embryos frozen, and 65 cycles (48.1%) had total embryo arrest. Results Analysis of patient baseline demographic data, cycle characteristics, and cycle outcomes for day3 transfer group and extended culture group indicated that a higher body mass index in the day3 transfer group was the only significant difference (p = 0.006). Both fresh transfer groups had low live birth rates (LBRs) (4.5% vs. 7.4% p = 0.46). After extended culture, 65 cycles (48.1%) were cancelled because the embryos exhibited developmental arrest and 70 cycles (51.9%) grew to day4 or day5. Thirteen frozen embryo transfer (FET) cycles and 22 frozen blastocysts derived from MPEs were thawed. There were more high-quality embryos (p < 0.001), higher implantation rates (IRs) (p = 0.038), and higher LBRs (p = 0.042) for embryos that underwent FET cycles. MPES in extended culture transfer have favorable survival than MPES in day3 transfer. Conclusion The extended culture of MPEs in fresh transfer cycles did not increase the LBR. However, younger females with the extended culture of MPEs followed by FET resulted in significantly higher LBRs and may be a feasible strategy to improve outcomes for patients with poor embryo quality. However, day3 embryo transfer may be a better choice if a fresh transfer is unrestricted and avoid the cycle cancellation. Extended culture may decrease to the transfer of developmental potential arrest embryos to patients.
Collapse
Affiliation(s)
- Pin-Yao Lin
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Lee Womens' Hospital, Taichung, Taiwan
| | - Chia-Yun Lin
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ni-Chin Tsai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Fu-Jen Huang
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hsin-Ju Chiang
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Ju Lin
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Ting Su
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Chung Lan
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| |
Collapse
|
41
|
Annie L, Gurusubramanian G, Roy VK. Inhibition of visfatin/NAMPT affects ovarian proliferation, apoptosis, and steroidogenesis in pre-pubertal mice ovary. J Steroid Biochem Mol Biol 2020; 204:105763. [PMID: 32987128 DOI: 10.1016/j.jsbmb.2020.105763] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 12/15/2022]
Abstract
Pubertal ovarian function might be dependent on the factors present in the pre-pubertal stages. Visfatin regulates ovarian steroidogenesis in adult. To date, no study has investigated the role of visfatin either in pre-pubertal or pubertal mice ovary. Thus, we investigated the role of visfatin in pre-pubertal mice ovary in relation to steroidogenesis and proliferation and apoptosis in vitro by inhibiting the endogenous visfatin by a specific inhibitor, FK866. Inhibition of visfatin increased the estrogen secretion and also up-regulated the expression of CYP11A1, 17βHSD and CYP19A1 in mice ovary. Furthermore, active caspase3 was up-regulated along with the down-regulation of BAX and BCL2 in the pre-pubertal ovary after visfatin inhibition. The expression of GCNA, PCNA, and BrdU labeling was also decreased by FK866 treatment. These results suggest that visfatin inhibits steroidogenesis, increases proliferation, and suppresses apoptosis in the pre-pubertal mice ovary. So, visfatin is a new regulator of ovary function in pre-pubertal mice.
Collapse
Affiliation(s)
| | | | - Vikas Kumar Roy
- Department of Zoology, Mizoram University, Aizawl, Mizoram 796 004, India.
| |
Collapse
|
42
|
Suzuki S, Diaz VD, Hermann BP. What has single-cell RNA-seq taught us about mammalian spermatogenesis? Biol Reprod 2020; 101:617-634. [PMID: 31077285 DOI: 10.1093/biolre/ioz088] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 05/09/2019] [Indexed: 12/18/2022] Open
Abstract
Mammalian spermatogenesis is a complex developmental program that transforms mitotic testicular germ cells (spermatogonia) into mature male gametes (sperm) for production of offspring. For decades, it has been known that this several-weeks-long process involves a series of highly ordered and morphologically recognizable cellular changes as spermatogonia proliferate, spermatocytes undertake meiosis, and spermatids develop condensed nuclei, acrosomes, and flagella. Yet, much of the underlying molecular logic driving these processes has remained opaque because conventional characterization strategies often aggregated groups of cells to meet technical requirements or due to limited capability for cell selection. Recently, a cornucopia of single-cell transcriptome studies has begun to lift the veil on the full compendium of gene expression phenotypes and changes underlying spermatogenic development. These datasets have revealed the previously obscured molecular heterogeneity among and between varied spermatogenic cell types and are reinvigorating investigation of testicular biology. This review describes the extent of available single-cell RNA-seq profiles of spermatogenic and testicular somatic cells, how those data were produced and evaluated, their present value for advancing knowledge of spermatogenesis, and their potential future utility at both the benchtop and bedside.
Collapse
Affiliation(s)
- Shinnosuke Suzuki
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas
| | - Victoria D Diaz
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas
| | - Brian P Hermann
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas
| |
Collapse
|
43
|
Chotiner JY, Wolgemuth DJ, Wang PJ. Functions of cyclins and CDKs in mammalian gametogenesis†. Biol Reprod 2020; 101:591-601. [PMID: 31078132 DOI: 10.1093/biolre/ioz070] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 04/10/2019] [Accepted: 04/17/2019] [Indexed: 12/13/2022] Open
Abstract
Cyclins and cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. Most of our understanding of their functions has been obtained from studies in single-cell organisms and mitotically proliferating cultured cells. In mammals, there are more than 20 cyclins and 20 CDKs. Although genetic ablation studies in mice have shown that most of these factors are dispensable for viability and fertility, uncovering their functional redundancy, CCNA2, CCNB1, and CDK1 are essential for embryonic development. Cyclin/CDK complexes are known to regulate both mitotic and meiotic cell cycles. While some mechanisms are common to both types of cell divisions, meiosis has unique characteristics and requirements. During meiosis, DNA replication is followed by two successive rounds of cell division. In addition, mammalian germ cells experience a prolonged prophase I in males or a long period of arrest in prophase I in females. Therefore, cyclins and CDKs may have functions in meiosis distinct from their mitotic functions and indeed, meiosis-specific cyclins, CCNA1 and CCNB3, have been identified. Here, we describe recent advances in the field of cyclins and CDKs with a focus on meiosis and early embryogenesis.
Collapse
Affiliation(s)
- Jessica Y Chotiner
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
- Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Debra J Wolgemuth
- Department of Genetics & Development, Columbia University Medical Center, New York, New York, USA
| | - P Jeremy Wang
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
- Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
44
|
Powering life through MitoTechnologies: exploring the bio-objectification of mitochondria in reproduction. BIOSOCIETIES 2020. [DOI: 10.1057/s41292-020-00204-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
AbstractMitochondria, the organelles providing the cell with energy, have recently gained greater public visibility in the UK and beyond, through the introduction of two reproductive technologies which involve their manipulation, specifically ‘mitochondrial donation’ to prevent the maternal transmission of inherited disorders, and ‘Augment’ to improve egg quality and fertility. Focusing on these two ‘MitoTechnologies’ and mobilising the conceptual framework of “bio-objectification”, we examine three key processes whereby mitochondria are made to appear to have a life of their own: their transferability, their optimisation of life processes and their capitalisation. We then explore the implications of their bio-objectification in the bioeconomy of reproduction. Drawing on publicly available material collected in two research projects, we argue that mitochondria become a biopolitical agent by contributing to the redefinition of life as something that can be boosted at the cellular level and in reproduction. Mitochondria are now presented as playing a key role for a successful and healthy conception through the development and promotion of MitoTechnologies. We also show how their “revitalising power” is invested with great promissory capital, mainly deriving from their ethical and scientific biovalue in the case of mitochondrial donation, and from the logics of assetisation, in the case of Augment.
Collapse
|
45
|
Sun X, Klinger FG, Liu J, De Felici M, Shen W, Sun X. miR-378-3p maintains the size of mouse primordial follicle pool by regulating cell autophagy and apoptosis. Cell Death Dis 2020; 11:737. [PMID: 32913213 PMCID: PMC7483766 DOI: 10.1038/s41419-020-02965-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 08/18/2020] [Accepted: 08/27/2020] [Indexed: 12/13/2022]
Abstract
Primordial follicle pool provides all available oocytes throughout the whole reproductive life span. Abnormal regulation in primordial follicle assembly leads to abnormal size of primordial follicle pool, even causes infertility. Here, miR-378-3p was proved to regulate mouse primordial follicle assembly both in vivo and in vitro. The expression of miR-378-3p significantly increased in mice ovaries from 17.5 dpc (days post coitum) up to 3 dpp (day post partum) compared with the expression of 16.5 dpc ovaries, which suggested that miR-378-3p was involved in primordial follicle assembly. To uncover the underlying mechanism, newborn mice ovaries were cultured in vitro in the presence of rapamycin and 3-methyladenine, which showed that the expression of miR-378-3p changed together with the percentage of primordial follicle. Moreover, during the normal process of primordial follicle assembly between 17.6 dpc and 3 dpp, autophagy is activated, while, apoptosis is inhibited. The in vivo results showed that newborn mice starved for 1.5 days showing the increased miR-378-3p, activated autophagy and inhibited apoptosis in the ovaries, had more percentage of primordial follicles. Over-expression of miR-378-3p using miR-378-3p agomir caused increased percentage of primordial follicle, increased level of autophagy, and decreased level of apoptosis. Knockdown of miR-378-3p by miR-378-3p antiagomir had the opposite results. Using pmirGLO Dual-Luciferase miRNA Target Expression system, we confirmed both PDK1 and Caspase9 were targets of miR-378-3p, which suggested that miR-378-3p activated autophagy by targeting PDK1 and inhibited apoptosis by targeting Caspase9. MiR-378-3p could be used as a biomarker of diseases caused by abnormal size of primordial follicle pool for diagnosis, prevention, or therapy.
Collapse
Affiliation(s)
- Xiaowen Sun
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, 266109, China.,College of Life Sciences, Qingdao Agricultural University, Qingdao, 266109, China
| | - Francesca Gioia Klinger
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 00133, Italy
| | - Jing Liu
- Central laboratory of Qingdao Agricultural University, Qingdao, 266109, China
| | - Massimo De Felici
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 00133, Italy
| | - Wei Shen
- College of Life Sciences, Qingdao Agricultural University, Qingdao, 266109, China
| | - Xiaofeng Sun
- College of Life Sciences, Qingdao Agricultural University, Qingdao, 266109, China.
| |
Collapse
|
46
|
Mondragon AA, Yalonetskaya A, Ortega AJ, Zhang Y, Naranjo O, Elguero J, Chung WS, McCall K. Lysosomal Machinery Drives Extracellular Acidification to Direct Non-apoptotic Cell Death. Cell Rep 2020; 27:11-19.e3. [PMID: 30943394 PMCID: PMC6613820 DOI: 10.1016/j.celrep.2019.03.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 02/18/2019] [Accepted: 03/08/2019] [Indexed: 02/07/2023] Open
Abstract
Cell death is a fundamental aspect of development, homeostasis, and disease; yet, our understanding of non-apoptotic forms of cell death is limited. One such form is phagoptosis, in which one cell utilizes phagocytosis machinery to kill another cell that would otherwise continue living. We have previously identified a non-autonomous requirement of phagocytosis machinery for the developmental programmed cell death of germline nurse cells in the Drosophila ovary; however, the precise mechanism of death remained elusive. Here, we show that lysosomal machinery acting in epithelial follicle cells is used to non-autonomously induce the death of nearby germline cells. Stretch follicle cells recruit V-ATPases and chloride channels to their plasma membrane to extracellularly acidify the germline and release cathepsins that destroy the nurse cells. Our results reveal a role for lysosomal machinery acting at the plasma membrane to cause the death of neighboring cells, providing insight into mechanisms driving non-autonomous cell death. Mondragon et al. show that V-ATPase proton pumps localize to the plasma membrane of follicle cells and promote extracellular acidification to eliminate adjacent nurse cells in the Drosophila ovary. The follicle cells subsequently release cathepsins by exocytosis into the nurse cells to promote their final degradation.
Collapse
Affiliation(s)
- Albert A Mondragon
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA; Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston, MA 02215, USA
| | - Alla Yalonetskaya
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
| | - Anthony J Ortega
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
| | - Yuanhang Zhang
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
| | - Oandy Naranjo
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
| | - Johnny Elguero
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
| | - Won-Suk Chung
- Department of Biological Sciences, KAIST, Daejeon, South Korea
| | - Kimberly McCall
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA.
| |
Collapse
|
47
|
A dual death/survival role of autophagy in the adult ovary of Lagostomus maximus (Mammalia- Rodentia). PLoS One 2020; 15:e0232819. [PMID: 32469908 PMCID: PMC7259749 DOI: 10.1371/journal.pone.0232819] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 04/22/2020] [Indexed: 12/16/2022] Open
Abstract
Follicular atresia is a cell death event that occurs in the great majority of follicles before ovulation in the mature mammalian ovary. Germ cell loss has been mainly associated to apoptosis although autophagy also seems to be at play. Aimed to increase our understanding on the possible cooperating role of autophagy and apoptosis in follicular atresia and/or follicular survival, we analyzed both programmed cell death mechanisms in a rodent model, the South American plains vizcacha, Lagostomus maximus. Female vizcacha shows highly suppressed apoptosis-dependent follicular atresia in the adult ovary, with continuous folliculogenesis and massive polyovulation. This strategy of massive ovulation requires a permanent remodeling of the ovarian architecture to maintain the availability of quiescent primordial follicles throughout the individual's reproductive lifespan. We report here our analysis of autophagy (BECN1, LAMP1 and LC3B-I/II) and apoptosis (BCL2 and ACTIVE CASPASE-3) markers which revealed interactive behaviors between both processes, with autophagy promoting survival or cell death depending on the ovarian structure. Strong BECN1, LC3B-II and LAMP1 staining was observed in atretic follicles and degenerating corpora lutea that also expressed nuclear ACTIVE CASPASE-3. Healthy follicles showed a slight expression of autophagy proteins but a strong expression of BCL2 and no detectable ACTIVE CASPASE-3. Transmission electron microscopy revealed a high formation of autophagosomes, autolysosomes and lysosomes in atretic follicles and degenerating corpora lutea and a low number of autophagic vesicles in normal follicles. The co-expression of LC3B-BECN1, LC3B-LAMP1 and LC3B-ACTIVE CASPASE-3 was only detected in atretic follicles and degenerating corpora lutea, while co-expression of BCL2-BECN1 was only observed in normal follicles. We propose that autophagy could act as a mechanism to eliminate altered follicles and remnant corpora lutea providing the necessary space for maturation of primordial follicles that continuously enter the growing follicular pool to sustain massive ovulation.
Collapse
|
48
|
Ghunaim S, Ghazeeri G, Khalife D, Azim HA. Fertility preservation in patients with BRCA mutation. Ecancermedicalscience 2020; 14:1033. [PMID: 32419845 PMCID: PMC7221131 DOI: 10.3332/ecancer.2020.1033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Indexed: 12/27/2022] Open
Abstract
Evidence suggests a likely negative impact of deleterious BRCA mutations on female fertility. Hence, different studies have aimed to address the reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients with a prime focus on their safety and efficacy. However, several uncertainties exist in many domains of this field. The aim of the current paper is to overview the reproductive potential and fertility preservation options in breast and ovarian cancer patients harbouring a BRCA mutation. We also discuss pre-implantation genetic testing in an attempt to help physicians during oncofertility counselling of these patients.
Collapse
Affiliation(s)
- Suleiman Ghunaim
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Haifa Idriss-ART Unit, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
| | - Ghina Ghazeeri
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Haifa Idriss-ART Unit, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
| | - Dalia Khalife
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Haifa Idriss-ART Unit, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
| | - Hatem A Azim
- Breast Cancer Centre, Hospital Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico
| |
Collapse
|
49
|
Martin JH, Aitken RJ, Bromfield EG, Nixon B. DNA damage and repair in the female germline: contributions to ART. Hum Reprod Update 2020; 25:180-201. [PMID: 30541031 DOI: 10.1093/humupd/dmy040] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/27/2018] [Accepted: 11/06/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND DNA integrity and stability are critical determinants of cell viability. This is especially true in the female germline, wherein DNA integrity underpins successful conception, embryonic development, pregnancy and the production of healthy offspring. However, DNA is not inert; rather, it is subject to assault from various environment factors resulting in chemical modification and/or strand breakage. If structural alterations result and are left unrepaired, they have the potential to cause mutations and propagate disease. In this regard, reduced genetic integrity of the female germline ranks among the leading causes of subfertility in humans. With an estimated 10% of couples in developed countries taking recourse to ART to achieve pregnancy, the need for ongoing research into the capacity of the oocyte to detect DNA damage and thereafter initiate cell cycle arrest, apoptosis or DNA repair is increasingly more pressing. OBJECTIVE AND RATIONALE This review documents our current knowledge of the quality control mechanisms utilised by the female germline to prevent and remediate DNA damage during their development from primordial follicles through to the formation of preimplantation embryos. SEARCH METHODS The PubMed database was searched using the keywords: primordial follicle, primary follicle, secondary follicle, tertiary follicle, germinal vesical, MI, MII oocyte, zygote, preimplantation embryo, DNA repair, double-strand break and DNA damage. These keywords were combined with other phrases relevant to the topic. Literature was restricted to peer-reviewed original articles in the English language (published 1979-2018) and references within these articles were also searched. OUTCOMES In this review, we explore the quality control mechanisms utilised by the female germline to prevent, detect and remediate DNA damage. We follow the trajectory of development from the primordial follicle stage through to the preimplantation embryo, highlighting findings likely to have important implications for fertility management, age-related subfertility and premature ovarian failure. In addition, we survey the latest discoveries regarding DNA repair within the metaphase II (MII) oocyte and implicate maternal stores of endogenous DNA repair proteins and mRNA transcripts as a primary means by which they defend their genomic integrity. The collective evidence reviewed herein demonstrates that the MII oocyte can engage in the activation of major DNA damage repair pathway(s), therefore encouraging a reappraisal of the long-held paradigm that oocytes are largely refractory to DNA repair upon reaching this late stage of their development. It is also demonstrated that the zygote can exploit a number of protective strategies to mitigate the risk and/or effect the repair, of DNA damage sustained to either parental germline; affirming that DNA protection is largely a maternally driven trait but that some aspects of repair may rely on a collaborative effort between the male and female germlines. WIDER IMPLICATIONS The present review highlights the vulnerability of the oocyte to DNA damage and presents a number of opportunities for research to bolster the stringency of the oocyte's endogenous defences, with implications extending to improved diagnostics and novel therapeutic applications to alleviate the burden of infertility.
Collapse
Affiliation(s)
- Jacinta H Martin
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, Kookaburra Circuit, New Lambton Heights, NSW, Australia
| | - R John Aitken
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, Kookaburra Circuit, New Lambton Heights, NSW, Australia
| | - Elizabeth G Bromfield
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, Kookaburra Circuit, New Lambton Heights, NSW, Australia
| | - Brett Nixon
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, Kookaburra Circuit, New Lambton Heights, NSW, Australia
| |
Collapse
|
50
|
Raei Sadigh A, Darabi M, Salmassi A, Hamdi K, Farzadi L, Ghasemzadeh A, Fattahi A, Nouri M. Fractalkine and apoptotic/anti-apoptotic markers in granulosa cells of women with polycystic ovarian syndrome. Mol Biol Rep 2020; 47:3593-3603. [PMID: 32350744 DOI: 10.1007/s11033-020-05452-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 04/09/2020] [Indexed: 12/29/2022]
Abstract
Owing to the role of fractalkine in regulating cellular apoptosis/proliferation, we investigated fractalkine effects on apoptosis/proliferation signaling of granulosa cells in polycystic ovarian syndrome (PCOS) patients through in vitro and in vivo experiments. In vivo, granulosa cells were collected from 40 women undergoing oocyte retrieval (20 controls and 20 PCOS). The expression levels of fractalkine, BAX, Bcl2, Bcl2-XL, Bad, and TNF-α were assessed using RT-PCR. In vitro, we determined the effect of different doses of fractalkine on the expression of the above mentioned genes in GCs of both groups. We found that the expression levels of fractalkine and Bcl-2 were significantly lower in the GCs of PCOS patients compared to the control group (p < 0.05). In contrast, the expression levels of TNF-α and BAX were higher in the patient's group than in the control group. The results suggested that expression levels of fractalkine were negatively and positively correlated with the number of oocytes and fertilized oocytes respectively. Moreover, fractalkine could dose-dependently increase fractalkine and decrease BAD, BAX, Bcl-xl, and TNF-α expressions in the control GCs. In contrast, GCs collected from PCOS patients revealed an increase in expression of BAD, BAX, and Bcl-xl following fractalkine treatment. Our findings indicated that insufficient expression of fractalkine in PCOS patients is related with elevated apoptotic and inflammatory markers and reduced anti-apoptotic genes in the GCs.
Collapse
Affiliation(s)
- Aydin Raei Sadigh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratory, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoud Darabi
- Department of Biochemistry and Clinical Laboratory, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Salmassi
- Department of Reproductive Biology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kobra Hamdi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Laya Farzadi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliye Ghasemzadeh
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Fattahi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Reproductive Biology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Biochemistry and Clinical Laboratory, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Reproductive Biology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|