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Li N, Du X, Zhao Y, Zeng Q, Han C, Xiong D, He L, Zhang G, Liu W. Exploring stem cell technology: Pioneering new pathways for female fertility preservation and restoration. Reprod Biol 2024; 24:100958. [PMID: 39393314 DOI: 10.1016/j.repbio.2024.100958] [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: 05/03/2024] [Revised: 09/24/2024] [Accepted: 09/28/2024] [Indexed: 10/13/2024]
Abstract
The fertility of women is crucial for the well-being of individuals and families. However, various factors such as chemotherapy, lifestyle changes, among others, may lead to a decline in female fertility, thus emphasizing the significance of preserving and restoring fertility. Stem cells, with their unique capacity for self-renewal and pluripotent differentiation, have made significant strides in areas such as ovarian tissue cryopreservation, in vitro culture of frozen-thawed ovarian tissue, and construction of ovarian-like organs. This review aims to summarize the latest findings in these fields, highlighting the pivotal role, mechanisms, and future prospects of stem cell technology in preserving and restoring female fertility. Additionally, the importance of interdisciplinary collaboration is underscored, as personalized stem cell therapy regimens tailored through interdisciplinary cooperation between reproductive medicine and stem cell fields hold promise in providing reliable solutions for the preservation and restoration of female fertility.
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Affiliation(s)
- Ningjing Li
- School of Medicine and life sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xinrong Du
- School of Medicine and life sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuhong Zhao
- College of Laboratory Medicine, Chengdu Medical College, Chengdu 610500, China
| | - Qin Zeng
- Sichuan Provincial Woman's and Children's Hospital / The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu 610045, China
| | - Changli Han
- School of Medicine and life sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Dongsheng Xiong
- Sichuan Provincial Woman's and Children's Hospital / The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu 610045, China
| | - Libing He
- Sichuan Provincial Woman's and Children's Hospital / The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu 610045, China
| | - Guohui Zhang
- Sichuan Provincial Woman's and Children's Hospital / The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu 610045, China.
| | - Weixin Liu
- Sichuan Provincial Woman's and Children's Hospital / The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu 610045, China.
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2
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Garg A, Seli E. Leukocyte telomere length and DNA methylome as biomarkers of ovarian reserve and embryo aneuploidy: the intricate relationship between somatic and reproductive aging. Fertil Steril 2024; 121:26-33. [PMID: 37979607 DOI: 10.1016/j.fertnstert.2023.11.011] [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: 09/01/2023] [Revised: 11/12/2023] [Accepted: 11/13/2023] [Indexed: 11/20/2023]
Abstract
The average childbearing age among women continues to rise, leading to an increased prevalence of infertility and a subsequent increased use of assisted reproductive technologies (ARTs). Ovarian aging, especially diminished ovarian reserve and poor ovarian response, have been implicated as common causes of infertility. Telomere length and DNA methylation-based epigenetic clocks are established hallmarks of cellular aging; however, the interplay between somatic and ovarian aging remains unclear. There appears to be a lack of correlation between leukocyte telomere length and the DNA methylation age of somatic and ovarian cells. Both the telomere length and methylome of follicular somatic cells (granulosa and cumulus) appear to be unaffected by chronologic age, infertility, or processes that result in diminished ovarian reserve and poor ovarian response. As such, they are unlikely candidates as surrogate biomarkers of reproductive potential, response to stimulation, or ART outcome. Meanwhile, telomere or methylome changes in leukocytes associated with aging seem to correlate with reproductive function and may have the potential to aid the characterization of women with reproductive decline; however, current data are limited and larger studies evaluating this within an ART setting are warranted.
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Affiliation(s)
- Akanksha Garg
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Emre Seli
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut; IVIRMA Global Research Alliance, IVIRMA New Jersey, Basking Ridge, New Jersey.
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Pellicer N, Cozzolino M, Diaz-García C, Galliano D, Cobo A, Pellicer A, Herraiz S. Ovarian rescue in women with premature ovarian insufficiency: facts and fiction. Reprod Biomed Online 2023; 46:543-565. [PMID: 36710157 DOI: 10.1016/j.rbmo.2022.12.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 11/16/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022]
Abstract
The ovary has a comparatively short functional lifespan compared with other organs, and genetic and pathological injuries can further shorten its functional life. Thus, preserving ovarian function should be considered in the context of women with threats to ovarian reserve, such as ageing, premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR). Indeed, one-third of women with POI retain resting follicles that can be reactivated to produce competent oocytes, as proved by the in-vitro activation of dormant follicles. This paper discusses mechanisms and clinical data relating to new therapeutic strategies using ovarian fragmentation, stem cells or platelet-rich plasma to regain ovarian function in women of older age (>38 years) or with POI or DOR. Follicle reactivation techniques show promising experimental outcomes and have been successful in some cases, when POI is established or DOR diagnosed; however, there is scarce clinical evidence to warrant their widespread clinical use. Beyond these contexts, also discussed is how new insights into the biological mechanisms governing follicular dynamics and oocyte competence may play a role in reversing ovarian damage, as no technique modifies oocyte quality. Additional studies should focus on increasing follicle number and quality. Finally, there is a small but important subgroup of women lacking residual follicles and requiring oocyte generation from stem cells.
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Affiliation(s)
| | | | - César Diaz-García
- IVI London, EGA Institute for Women's Health, UCL, London, UK; IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | | | - Ana Cobo
- IVI RMA Valencia, Valencia, Spain
| | - Antonio Pellicer
- IVI RMA Rome, Rome, Italy; IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Sonia Herraiz
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
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Zhu Z, Xu W, Liu L. Ovarian aging: mechanisms and intervention strategies. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:590-610. [PMID: 37724254 PMCID: PMC10471094 DOI: 10.1515/mr-2022-0031] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 10/25/2022] [Indexed: 09/20/2023]
Abstract
Ovarian reserve is essential for fertility and influences healthy aging in women. Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes. The molecular mechanisms and various contributing factors underlying ovarian aging have been uncovered. In this review, we highlight some of critical factors that impact oocyte quantity and quality during aging. Germ cell and follicle reserve at birth determines reproductive lifespan and timing the menopause in female mammals. Accelerated diminishing ovarian reserve leads to premature ovarian aging or insufficiency. Poor oocyte quality with increasing age could result from chromosomal cohesion deterioration and misaligned chromosomes, telomere shortening, DNA damage and associated genetic mutations, oxidative stress, mitochondrial dysfunction and epigenetic alteration. We also discuss the intervention strategies to delay ovarian aging. Both the efficacy of senotherapies by antioxidants against reproductive aging and mitochondrial therapy are discussed. Functional oocytes and ovarioids could be rejuvenated from pluripotent stem cells or somatic cells. We propose directions for future interventions. As couples increasingly begin delaying parenthood in life worldwide, understanding the molecular mechanisms during female reproductive aging and potential intervention strategies could benefit women in making earlier choices about their reproductive health.
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Affiliation(s)
- Zhengmao Zhu
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, China
| | - Wanxue Xu
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Lin Liu
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Tianjin Union Medical Center, Institute of Translational Medicine, Nankai University, Tianjin, China
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Stem Cell-Based Therapeutic Strategies for Premature Ovarian Insufficiency and Infertility: A Focus on Aging. Cells 2022; 11:cells11233713. [PMID: 36496972 PMCID: PMC9738202 DOI: 10.3390/cells11233713] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Reproductive aging is on the rise globally and inseparable from the entire aging process. An extreme form of reproductive aging is premature ovarian insufficiency (POI), which to date has mostly been of idiopathic etiology, thus hampering further clinical applications and associated with enormous socioeconomic and personal costs. In the field of reproduction, the important functional role of inflammation-induced ovarian deterioration and therapeutic strategies to prevent ovarian aging and increase its function are current research hotspots. This review discusses the general pathophysiology and relative causes of POI and comprehensively describes the association between the aging features of POI and infertility. Next, various preclinical studies of stem cell therapies with potential for POI treatment and their molecular mechanisms are described, with particular emphasis on the use of human induced pluripotent stem cell (hiPSC) technology in the current scenario. Finally, the progress made in the development of hiPSC technology as a POI research tool for engineering more mature and functional organoids suitable as an alternative therapy to restore infertility provides new insights into therapeutic vulnerability, and perspectives on this exciting research on stem cells and the derived exosomes towards more effective POI diagnosis and treatment are also discussed.
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Liu C, Moten A, Ma Z, Lin HK. The foundational framework of tumors: Gametogenesis, p53, and cancer. Semin Cancer Biol 2022; 81:193-205. [PMID: 33940178 PMCID: PMC9382687 DOI: 10.1016/j.semcancer.2021.04.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 04/20/2021] [Accepted: 04/26/2021] [Indexed: 12/20/2022]
Abstract
The completion-of-tumor hypothesis involved in the dynamic interplay between the initiating oncogenic event and progression is essential to better recognize the foundational framework of tumors. Here we review and extend the gametogenesis-related hypothesis of tumors, because high embryonic/germ cell traits are common in tumors. The century-old gametogenesis-related hypothesis of tumors postulated that tumors arise from displaced/activated trophoblasts, displaced (lost) germ cells, and the reprogramming/reactivation of gametogenic program in somatic cells. Early primordial germ cells (PGCs), embryonic stem (ES) cells, embryonic germ cells (EGCs), and pre-implantation embryos at the stage from two-cell stage to blastocysts originating from fertilization or parthenogenesis have the potential to develop teratomas/teratocarcinomas. In addition, the teratomas/teratocarcinomas/germ cells occur in gonads and extra-gonads. Undoubtedly, the findings provide strong support for the hypothesis. However, it was thought that these tumor types were an exception rather than verification. In fact, there are extensive similarities between somatic tumor types and embryonic/germ cell development, such as antigens, migration, invasion, and immune escape. It was documented that embryonic/germ cell genes play crucial roles in tumor behaviors, e.g. tumor initiation and metastasis. Of note, embryonic/germ cell-like tumor cells at different developmental stages including PGC and oocyte to the early embryo-like stage were identified in diverse tumor types by our group. These embryonic/germ cell-like cancer cells resemble the natural embryonic/germ cells in morphology, gene expression, the capability of teratoma formation, and the ability to undergo the process of oocyte maturation and parthenogenesis. These embryonic/germ cell-like cancer cells are derived from somatic cells and contribute to tumor formation, metastasis, and drug resistance, establishing asexual meiotic embryonic life cycle. p53 inhibits the reactivation of embryonic/germ cell state in somatic cells and oocyte-like cell maturation. Based on earlier and our recent studies, we propose a novel model to complete the gametogenesis-related hypothesis of tumors, which can be applied to certain somatic tumors. That is, tumors tend to establish a somatic asexual meiotic embryonic cycle through the activation of somatic female gametogenesis and parthenogenesis in somatic tumor cells during the tumor progression, thus passing on corresponding embryonic/germ cell traits leading to the malignant behaviors and enhancing the cells' independence. This concept may be instrumental to better understand the nature and evolution of tumors. We rationalize that targeting the key events of somatic pregnancy is likely a better therapeutic strategy for cancer treatment than directly targeting cell mitotic proliferation, especially for those tumors with p53 inactivation.
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Affiliation(s)
- Chunfang Liu
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
| | - Asad Moten
- Medical Sciences Division, University of Oxford, Oxford OX3 9DU, UK
| | - Zhan Ma
- Department of Laboratory Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China
| | - Hui-Kuan Lin
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
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Role of Stem Cells in the Ovarian Tissue Cryopreservation and Transplantation for Fertility Preservation. Int J Mol Sci 2021; 22:ijms222212482. [PMID: 34830363 PMCID: PMC8620430 DOI: 10.3390/ijms222212482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/13/2021] [Accepted: 11/15/2021] [Indexed: 11/17/2022] Open
Abstract
Although the cancer survival rate has increased, cancer treatments, including chemotherapy and radiotherapy, can cause ovarian failure and infertility in women of reproductive age. Preserving fertility throughout cancer treatment is critical for maintaining quality of life. Fertility experts should propose individualized fertility preservation methods based on the patient’s marital status, pubertal status, partner status, and the urgency of treatment. Widely practiced fertility preservation methods, including ovarian transposition and embryo and oocyte cryopreservation, are inappropriate for prepubertal girls or those needing urgent initiation of cancer treatment. Ovarian tissue cryopreservation and transplantation, an emerging new technology, may be a solution for these cancer patients. The use of stem cells in ovarian tissue cryopreservation and transplantation increases oxygenation, angiogenesis, and follicle survival rates. This review discusses the recent advances in ovarian tissue cryopreservation and transplantation with special focus on the use of stem cells to improve fertilization techniques.
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Sfakianoudis K, Rapani A, Grigoriadis S, Retsina D, Maziotis E, Tsioulou P, Giannelou P, Pantos K, Koutsilieris M, Vlahos N, Mastorakos G, Simopoulou M. Novel Approaches in Addressing Ovarian Insufficiency in 2019: Are We There Yet? Cell Transplant 2021; 29:963689720926154. [PMID: 32686983 PMCID: PMC7563844 DOI: 10.1177/0963689720926154] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Ovarian insufficiency is described as a multifaceted issue typically encountered in the field of assisted reproduction. The three main identified diagnoses of ovarian insufficiency include premature ovarian failure (POF), poor ovarian response (POR), and advanced maternal age (AMA). Patient heterogeneity in the era of individualized medicine drives research forward leading to the emergence of novel approaches. This plethora of innovative treatments in the service of adequately managing ovarian insufficiency is called to undertake the challenge of addressing infertile patients exploring their reproductive options. This review provides an all-inclusive presentation and critical analysis on novel treatments that have not achieved routine clinical practice status yet, but have recently emerged as promising. In light of the lack of randomized controlled trials conveying safety and efficiency, clinicians are left puzzled in addressing the "how" and "for whom" these approaches may be beneficial. From ovarian injection employing platelet-rich plasma (PRP) or stem cells to artificial gametes and ovaries, ovarian transplantation, and mitochondrial replacement therapy, this descriptive review provides insight toward assisting the practitioner in decision making regarding these cutting-edge treatments. Biological mechanisms, invasiveness levels, efficiency, as well as possible complications, the current status along with bioethical concerns are discussed in the context of identifying future optimal treatment.
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Affiliation(s)
| | - Anna Rapani
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Sokratis Grigoriadis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Retsina
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Unit of Endocrinology, Diabetes Mellitus and Metabolism, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Maziotis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Petroula Tsioulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Polina Giannelou
- Centre for Human Reproduction, Genesis Athens Clinic, Athens, Greece.,Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Vlahos
- Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George Mastorakos
- Unit of Endocrinology, Diabetes Mellitus and Metabolism, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Mara Simopoulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.,Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Emerging follicular activation strategies to treat women with poor ovarian response and primary ovarian insufficiency. Curr Opin Obstet Gynecol 2021; 33:241-248. [PMID: 33896920 DOI: 10.1097/gco.0000000000000703] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF THE REVIEW Female reproductive aging remains one of the key unsolved challenges in the field of reproductive medicine. This article reviews three of the most recent and cutting-edge strategies that are currently being investigated to address the issues of poor ovarian response (POR) and primary ovarian insufficiency (POI). RECENT FINDINGS Publications revealing the mechanism of mechanical disruption of the Hippo signaling pathway paved the way to studies on its potential application for fertility treatments. This, in combination with Akt stimulation, resulted in live births and ongoing pregnancies in women with POI. Building on previous reports on the effects of bone marrow transplants on fertility after chemotherapy, another approach involved autologous stem cell ovarian transplantation (ASCOT). The method proved effective in achieving live births in women previously diagnosed with POR. A third approach, intraovarian injection of autologous platelet-rich plasma, resulted in live births and ongoing pregnancies both spontaneously and via in vitro fertilization (IVF) in women with POI and POR. SUMMARY New paths are being charted to address the issues of POI and POR. Although these are preliminary studies that should be interpreted with caution, they represent great promise for the women affected by these conditions and the physicians treating them.
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Regenerative Medicine Approaches in Bioengineering Female Reproductive Tissues. Reprod Sci 2021; 28:1573-1595. [PMID: 33877644 DOI: 10.1007/s43032-021-00548-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/15/2021] [Indexed: 10/21/2022]
Abstract
Diseases, disorders, and dysfunctions of the female reproductive tract tissues can result in either infertility and/or hormonal imbalance. Current treatment options are limited and often do not result in tissue function restoration, requiring alternative therapeutic approaches. Regenerative medicine offers potential new therapies through the bioengineering of female reproductive tissues. This review focuses on some of the current technologies that could address the restoration of functional female reproductive tissues, including the use of stem cells, biomaterial scaffolds, bio-printing, and bio-fabrication of tissues or organoids. The use of these approaches could also be used to address issues in infertility. Strategies such as cell-based hormone replacement therapy could provide a more natural means of restoring normal ovarian physiology. Engineering of reproductive tissues and organs could serve as a powerful tool for correcting developmental anomalies. Organ-on-a-chip technologies could be used to perform drug screening for personalized medicine approaches and scientific investigations of the complex physiological interactions between the female reproductive tissues and other organ systems. While some of these technologies have already been developed, others have not been translated for clinical application. The continuous evolution of biomaterials and techniques, advances in bioprinting, along with emerging ideas for new approaches, shows a promising future for treating female reproductive tract-related disorders and dysfunctions.
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Poppe K, Bisschop P, Fugazzola L, Minziori G, Unuane D, Weghofer A. 2021 European Thyroid Association Guideline on Thyroid Disorders prior to and during Assisted Reproduction. Eur Thyroid J 2021; 9:281-295. [PMID: 33718252 PMCID: PMC7923920 DOI: 10.1159/000512790] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022] Open
Abstract
Severe thyroid dysfunction may lead to menstrual disorders and subfertility. Fertility problems may persist even after restoring normal thyroid function, and then an assisted reproductive technology (ART) may be a solution. Prior to an ART treatment, ovarian stimulation is performed, leading to high oestradiol levels, which may lead to hypothyroidism in women with thyroid autoimmunity (TAI), necessitating levothyroxine (LT4) supplements before pregnancy. Moreover, women with the polycystic ovarian syndrome and idiopathic subfertility have a higher prevalence of TAI. Women with hypothyroidism treated with LT4 prior to ART should have a serum TSH level <2.5 mIU/L. Subfertile women with hyperthyroidism planning an ART procedure should be informed of the increased risk of maternal and foetal complications, and euthyroidism should be restored and maintained for several months prior to an ART treatment. Fertilisation rates and embryo quality may be impaired in women with TSH >4.0 mIU/L and improved with LT4 therapy. In meta-analyses that mainly included women with TSH levels >4.0 mIU/L, LT4 treatment increased live birth rates, but that was not the case in 2 recent interventional studies in euthyroid women with TAI. The importance of the increased use of intracytoplasmic sperm injection as a type of ART on pregnancy outcomes in women with TAI deserves more investigation. For all of the above reasons, women of subfertile couples should be screened routinely for the presence of thyroid disorders.
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Affiliation(s)
- Kris Poppe
- Endocrine Unit, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium
- *Kris Poppe, Endocrine Unit, University Hospital CHU-St-Pierre, Université Libre de Bruxelles (ULB), Rue Haute 322, BE–1000 Bruxelles (Belgium),
| | - Peter Bisschop
- Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Laura Fugazzola
- Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Gesthimani Minziori
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - David Unuane
- Department of Internal Medicine, Endocrine Unit, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Andrea Weghofer
- Department of Gynecological Endocrinology & Reproductive Medicine, Medical University of Vienna, Vienna, Austria
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Diminished Ovarian Reserve Chemotherapy-Induced Mouse Model: A Tool for the Preclinical Assessment of New Therapies for Ovarian Damage. Reprod Sci 2020; 27:1609-1619. [PMID: 32430713 DOI: 10.1007/s43032-020-00191-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are primary factors leading to infertility. However, there is a lack of appropriate animal models of DOR usable for assessing new therapeutic strategies. In this study, we aimed to evaluate whether chemotherapy treatment in mice could reproduce features similar of that observed in women with DOR. Twenty-one Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) female mice were allocated to 3 groups (n = 7/group): control, single dose of vehicle (Dimethyl Sulfoxide [DMSO]); DOR, single reduced chemotherapy dose; and POI, single standard chemotherapy dose. After 21 days, mice underwent ovarian hyperstimulation and mating. Part of the animals were harvested to analyze ovarian reserve, ovulation and fertilization rates, and morphology, apoptosis, and vascularization of the ovarian stroma. The remaining mice underwent multiple matings to assess pregnancy rates and litter sizes. The DOR and POI mice showed an impaired estrous cyclicity and a decrease in ovarian mass, number of follicles, Metaphase II (MII) oocytes, and embryos as well as in ovarian stroma vascularization. Mice in both models showed also an increase in the percentage of morphologically abnormal follicles, stromal degeneration, and apoptosis. Similar to that observed in DOR and POI patients, these impairments were less severe in DOR than in POI mice. None of the POI females were able to achieve a pregnancy. Meanwhile, DOR females achieved several consecutive pregnancies, although litter size was decreased when compared to controls. In conclusion, a mouse model which displayed most of the ovarian characteristics and fertility outcomes of women with DOR has been established using a single dose of chemotherapy.
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13
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Germline Stem Cells Drive Ovary Regeneration in Zebrafish. Cell Rep 2020; 26:1709-1717.e3. [PMID: 30759383 DOI: 10.1016/j.celrep.2019.01.061] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 12/20/2018] [Accepted: 01/16/2019] [Indexed: 12/20/2022] Open
Abstract
Germline stem cells (GSCs) sustain gametogenesis during the organismal life cycle. Although evidence suggests that GSCs are consistently present in the zebrafish ovary and support oogenesis, whether GSCs are involved in zebrafish ovary regeneration is poorly understood. Here, we found that nanos2, a conserved vertebrate GSC marker, is required for maintaining GSCs in zebrafish. We applied genetic ablation and tissue resection techniques to delineate the function of GSCs in zebrafish ovary regeneration. After GSC ablation, ovaries fail to regenerate and are converted to sterile testes. Amputated ovarian tissues completely regenerate as a result of the proliferation of residual GSCs, but nanos2 mutant ovaries fail to regenerate after amputation due to a lack of GSCs. The repression of Wnt signaling leads to reduced numbers of GSCs and delayed ovary regeneration. Our results provide insight into the key role of GSCs in driving ovary regeneration.
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14
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Zhang M, Liu L, Cao X, Liu Y, Di J, Huang X, Sun F, Huang W, Xu F. Efficiently accumulating germ-like stem cells from mouse postnatal ovary by in situ tissue culture. Dev Growth Differ 2020; 62:223-231. [PMID: 32189336 DOI: 10.1111/dgd.12656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 01/15/2020] [Accepted: 01/20/2020] [Indexed: 11/27/2022]
Abstract
Although recent studies have revealed that germline stem cells (GSCs) exist in the mouse postnatal ovary, how to efficiently obtain GSCs for regenerating neo-oogenesis is still a technical challenge. Here, we report that using in situ tissue culture we can efficiently accumulate large amounts of proliferating germ-like cells from mouse postnatal ovaries. Usually, more than 10,000 germ-like cells can be derived from one ovary by this method, and over 20% of these cells can grow into germ-like cells with self-renewal, which thus can serve as a good cell pool to isolate GSCs by other cell assorting methods such as FACS. This method is simple and time-saving, which should be useful for in future studies on mouse GSCs.
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Affiliation(s)
- Meizi Zhang
- Reproductive Medicine Center, Tianjin First Central Hospital, Tianjin, China
| | - Li Liu
- Reproductive Medicine Center, Tianjin First Central Hospital, Tianjin, China
| | - Xiaomin Cao
- Reproductive Medicine Center, Tianjin First Central Hospital, Tianjin, China
| | - Ye Liu
- Reproductive Medicine Center, Tianjin First Central Hospital, Tianjin, China
| | - Jianyong Di
- Reproductive Medicine Center, Tianjin First Central Hospital, Tianjin, China
| | - Xiuying Huang
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Fangzhen Sun
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Weihong Huang
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Fengqin Xu
- Reproductive Medicine Center, Tianjin First Central Hospital, Tianjin, China
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15
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Mariniello K, Ruiz-Babot G, McGaugh EC, Nicholson JG, Gualtieri A, Gaston-Massuet C, Nostro MC, Guasti L. Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System. Front Endocrinol (Lausanne) 2019; 10:772. [PMID: 31781041 PMCID: PMC6856655 DOI: 10.3389/fendo.2019.00772] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 10/23/2019] [Indexed: 12/15/2022] Open
Abstract
The endocrine system coordinates a wide array of body functions mainly through secretion of hormones and their actions on target tissues. Over the last decades, a collective effort between developmental biologists, geneticists, and stem cell biologists has generated a wealth of knowledge related to the contribution of stem/progenitor cells to both organogenesis and self-renewal of endocrine organs. This review provides an up-to-date and comprehensive overview of the role of tissue stem cells in the development and self-renewal of endocrine organs. Pathways governing crucial steps in both development and stemness maintenance, and that are known to be frequently altered in a wide array of endocrine disorders, including cancer, are also described. Crucially, this plethora of information is being channeled into the development of potential new cell-based treatment modalities for endocrine-related illnesses, some of which have made it through clinical trials.
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Affiliation(s)
- Katia Mariniello
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Gerard Ruiz-Babot
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, United States
- Harvard Stem Cell Institute, Cambridge, MA, United States
| | - Emily C. McGaugh
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - James G. Nicholson
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Angelica Gualtieri
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Carles Gaston-Massuet
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Maria Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Leonardo Guasti
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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16
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Vermeulen M, Giudice MG, Del Vento F, Wyns C. Role of stem cells in fertility preservation: current insights. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2019; 12:27-48. [PMID: 31496751 PMCID: PMC6689135 DOI: 10.2147/sccaa.s178490] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/24/2019] [Indexed: 12/11/2022]
Abstract
While improvements made in the field of cancer therapy allow high survival rates, gonadotoxicity of chemo- and radiotherapy can lead to infertility in male and female pre- and postpubertal patients. Clinical options to preserve fertility before starting gonadotoxic therapies by cryopreserving sperm or oocytes for future use with assisted reproductive technology (ART) are now applied worldwide. Cryopreservation of pre- and postpubertal ovarian tissue containing primordial follicles, though still considered experimental, has already led to the birth of healthy babies after autotransplantation and is performed in an increasing number of centers. For prepubertal boys who do not produce gametes ready for fertilization, cryopreservation of immature testicular tissue (ITT) containing spermatogonial stem cells may be proposed as an experimental strategy with the aim of restoring fertility. Based on achievements in nonhuman primates, autotransplantation of ITT or testicular cell suspensions appears promising to restore fertility of young cancer survivors. So far, whether in two- or three-dimensional culture systems, in vitro maturation of immature male and female gonadal cells or tissue has not demonstrated a capacity to produce safe gametes for ART. Recently, primordial germ cells have been generated from embryonic and induced pluripotent stem cells, but further investigations regarding efficiency and safety are needed. Transplantation of mesenchymal stem cells to improve the vascularization of gonadal tissue grafts, increase the colonization of transplanted cells, and restore the damaged somatic compartment could overcome the current limitations encountered with transplantation.
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Affiliation(s)
- Maxime Vermeulen
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium
| | - Maria-Grazia Giudice
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium.,Department of Gynecology-Andrology, Cliniques Universitaires Saint-Luc, Brussels 1200, Belgium
| | - Federico Del Vento
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium
| | - Christine Wyns
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium.,Department of Gynecology-Andrology, Cliniques Universitaires Saint-Luc, Brussels 1200, Belgium
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17
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Sills ES, Wood SH. Autologous activated platelet-rich plasma injection into adult human ovary tissue: molecular mechanism, analysis, and discussion of reproductive response. Biosci Rep 2019; 39:BSR20190805. [PMID: 31092698 PMCID: PMC6549090 DOI: 10.1042/bsr20190805] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/09/2019] [Accepted: 05/14/2019] [Indexed: 01/19/2023] Open
Abstract
In clinical infertility practice, one intractable problem is low (or absent) ovarian reserve which in turn reflects the natural oocyte depletion associated with advancing maternal age. The number of available eggs has been generally thought to be finite and strictly limited, an entrenched and largely unchallenged tenet dating back more than 50 years. In the past decade, it has been suggested that renewable ovarian germline stem cells (GSCs) exist in adults, and that such cells may be utilized as an oocyte source for women seeking to extend fertility. Currently, the issue of whether mammalian females possess such a population of renewable GSCs remains unsettled. The topic is complex and even agreement on a definitive approach to verify the process of 'ovarian rescue' or 're-potentiation' has been elusive. Similarities have been noted between wound healing and ovarian tissue repair following capsule rupture at ovulation. In addition, molecular signaling events which might be necessary to reverse the effects of reproductive ageing seem congruent with changes occurring in tissue injury responses elsewhere. Recently, clinical experience with such a technique based on autologous activated platelet-rich plasma (PRP) treatment of the adult human ovary has been reported. This review summarizes the present state of understanding of the interaction of platelet-derived growth factors with adult ovarian tissue, and the outcome of human reproductive potential following PRP treatment.
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Affiliation(s)
- E Scott Sills
- Gen 5 Fertility Center, Office for Reproductive Research, Center for Advanced Genetics; San Diego, CA, U.S.A.
- Applied Biotechnology Research Group, University of Westminster; London W1B 2HW, U.K
| | - Samuel H Wood
- Gen 5 Fertility Center, Office for Reproductive Research, Center for Advanced Genetics; San Diego, CA, U.S.A
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18
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Akahori T, Woods DC, Tilly JL. Female Fertility Preservation through Stem Cell-based Ovarian Tissue Reconstitution In Vitro and Ovarian Regeneration In Vivo. CLINICAL MEDICINE INSIGHTS. REPRODUCTIVE HEALTH 2019; 13:1179558119848007. [PMID: 31191070 PMCID: PMC6540489 DOI: 10.1177/1179558119848007] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 03/27/2019] [Indexed: 12/13/2022]
Abstract
Historically, approaches designed to offer women diagnosed with cancer the prospects of having a genetically matched child after completion of their cytotoxic treatments focused on the existing oocyte population as the sole resource available for clinical management of infertility. In this regard, elective oocyte and embryo cryopreservation, as well as autologous ovarian cortical tissue grafting posttreatment, have gained widespread support as options for young girls and reproductive-age women who are faced with cancer to consider. In addition, the use of ovarian protective therapies, including gonadotropin-releasing hormone agonists and sphingosine-1-phosphate analogs, has been put forth as an alternative way to preserve fertility by shielding existing oocytes in the ovaries in vivo from the side-effect damage caused by radiotherapy and many chemotherapeutic regimens. This viewpoint changed with the publication of now numerous reports that adult ovaries of many mammalian species, including humans, contain a rare population of oocyte-producing germ cells-referred to as female germline or oogonial stem cells (OSCs). This new line of study has fueled research into the prospects of generating new oocytes, rather than working with existing oocytes, as a novel approach to sustain or restore fertility in female cancer survivors. Here, we overview the history of work from laboratories around the world focused on improving our understanding of the biology of OSCs and how these cells may be used to reconstitute "artificial" ovarian tissue in vitro or to regenerate damaged ovarian tissue in vivo as future fertility-preservation options.
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Affiliation(s)
- Taichi Akahori
- Laboratory for Aging and Infertility Research, Department of Biology, Northeastern University, Boston, MA, USA.,On leave from the Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Dori C Woods
- Laboratory for Aging and Infertility Research, Department of Biology, Northeastern University, Boston, MA, USA
| | - Jonathan L Tilly
- Laboratory for Aging and Infertility Research, Department of Biology, Northeastern University, Boston, MA, USA
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19
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Buigues A, Marchante M, Herraiz S, Pellicer A. Diminished Ovarian Reserve Chemotherapy-Induced Mouse Model: A Tool for the Preclinical Assessment of New Therapies for Ovarian Damage. Reprod Sci 2019:1933719119831784. [PMID: 30791852 DOI: 10.1177/1933719119831784] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are primary factors leading to infertility. However, there is a lack of appropriate animal models of DOR usable for assessing new therapeutic strategies. In this study, we aimed to evaluate whether chemotherapy treatment in mice could reproduce features similar of that observed in women with DOR. Twenty-one Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) female mice were allocated to 3 groups (n = 7/group): control, single dose of vehicle (Dimethyl Sulfoxide [DMSO]); DOR, single reduced chemotherapy dose; and POI, single standard chemotherapy dose. After 21 days, mice underwent ovarian hyperstimulation and mating. Part of the animals were harvested to analyze ovarian reserve, ovulation and fertilization rates, and morphology, apoptosis, and vascularization of the ovarian stroma. The remaining mice underwent multiple matings to assess pregnancy rates and litter sizes. The DOR and POI mice showed an impaired estrous cyclicity and a decrease in ovarian mass, number of follicles, Metaphase II (MII) oocytes, and embryos as well as in ovarian stroma vascularization. Mice in both models showed also an increase in the percentage of morphologically abnormal follicles, stromal degeneration, and apoptosis. Similar to that observed in DOR and POI patients, these impairments were less severe in DOR than in POI mice. None of the POI females were able to achieve a pregnancy. Meanwhile, DOR females achieved several consecutive pregnancies, although litter size was decreased when compared to controls. In conclusion, a mouse model which displayed most of the ovarian characteristics and fertility outcomes of women with DOR has been established using a single dose of chemotherapy.
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Affiliation(s)
- Anna Buigues
- 1 IVI Foundation, Valencia Spain
- 2 Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, Valencia University, Valencia, Spain
| | - Maria Marchante
- 1 IVI Foundation, Valencia Spain
- 2 Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, Valencia University, Valencia, Spain
| | - Sonia Herraiz
- 1 IVI Foundation, Valencia Spain
- 3 Reproductive Medicine Research Group, IIS La Fe, Valencia, Spain
- 4 IVI-RMA Valencia, Valencia, Spain
| | - Antonio Pellicer
- 1 IVI Foundation, Valencia Spain
- 3 Reproductive Medicine Research Group, IIS La Fe, Valencia, Spain
- 5 IVI-RMA Rome, Rome, Italy
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20
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Martin JJ, Woods DC, Tilly JL. Implications and Current Limitations of Oogenesis from Female Germline or Oogonial Stem Cells in Adult Mammalian Ovaries. Cells 2019; 8:E93. [PMID: 30696098 PMCID: PMC6407002 DOI: 10.3390/cells8020093] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 01/16/2019] [Indexed: 12/15/2022] Open
Abstract
A now large body of evidence supports the existence of mitotically active germ cells in postnatal ovaries of diverse mammalian species, including humans. This opens the possibility that adult stem cells naturally committed to a germline fate could be leveraged for the production of female gametes outside of the body. The functional properties of these cells, referred to as female germline or oogonial stem cells (OSCs), in ovaries of women have recently been tested in various ways, including a very recent investigation of the differentiation capacity of human OSCs at a single cell level. The exciting insights gained from these experiments, coupled with other data derived from intraovarian transplantation and genetic tracing analyses in animal models that have established the capacity of OSCs to generate healthy eggs, embryos and offspring, should drive constructive discussions in this relatively new field to further exploring the value of these cells to the study, and potential management, of human female fertility. Here, we provide a brief history of the discovery and characterization of OSCs in mammals, as well as of the in-vivo significance of postnatal oogenesis to adult ovarian function. We then highlight several key observations made recently on the biology of OSCs, and integrate this information into a broader discussion of the potential value and limitations of these adult stem cells to achieving a greater understanding of human female gametogenesis in vivo and in vitro.
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Affiliation(s)
- Jessica J Martin
- Laboratory of Aging and Infertility Research, Department of Biology, Northeastern University, Boston, MA 02115, USA.
| | - Dori C Woods
- Laboratory of Aging and Infertility Research, Department of Biology, Northeastern University, Boston, MA 02115, USA.
| | - Jonathan L Tilly
- Laboratory of Aging and Infertility Research, Department of Biology, Northeastern University, Boston, MA 02115, USA.
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21
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Herraiz S, Buigues A, Díaz-García C, Romeu M, Martínez S, Gómez-Seguí I, Simón C, Hsueh AJ, Pellicer A. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril 2018; 109:908-918.e2. [PMID: 29576341 DOI: 10.1016/j.fertnstert.2018.01.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 12/20/2017] [Accepted: 01/04/2018] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To assess if infusion of human bone marrow-derived stem cells (BMDSCs) could promote follicle development in patients with impaired ovarian functions. DESIGN Experimental design. SETTING University research laboratories. ANIMAL(S) Immunodeficient NOD/SCID female mice. INTERVENTION(S) Human BMDSCs were injected into mice with chemotherapy-induced ovarian damage and into immunodeficient mice xenografted with human cortex from poor-responder patients (PRs). MAIN OUTCOME MEASURE(S) Follicle development, ovulation, and offspring. Apoptosis, proliferation, and vascularization were evaluated in mouse and human ovarian stroma. RESULT(S) Fertility rescue and spontaneous pregnancies were achieved in mice ovaries mimicking PRs and ovarian insufficiency, induced by chemotherapy, after BMDSC infusion. Furthermore, BMDSC treatment resulted in production of higher numbers of preovulatory follicles, metaphase II oocytes, 2-cell embryos, and healthy pups. Stem cells promoted ovarian vascularization and cell proliferation, along with reduced apoptosis. In xenografted human ovarian tissues from PRs, infusion of BMDSCs and their CD133+ fraction led to their engraftment close to follicles, resulting in promotion of follicular growth, increases in E2 secretion, and enhanced local vascularization. CONCLUSION(S) Our results raised the possibility that promoting ovarian angiogenesis by BMDSC infusion could be an alternative approach to improve follicular development in women with impaired ovarian function. CLINICAL TRIAL REGISTRATION NUMBER NCT02240342.
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Affiliation(s)
- Sonia Herraiz
- IVI Foundation, Valencia, Spain; Reproductive Medicine Research Group, Valencia, Spain; Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain.
| | - Anna Buigues
- IVI Foundation, Valencia, Spain; Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain
| | - César Díaz-García
- Reproductive Medicine Research Group, Valencia, Spain; Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain; IVI London, London, United Kingdom
| | - Mónica Romeu
- Reproductive Medicine Research Group, Valencia, Spain
| | | | - Inés Gómez-Seguí
- Hematology Department, La Fe University Hospital, Valencia, Spain
| | - Carlos Simón
- Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain; Instituto Universitario IVI/INCLIVA, Valencia, Spain; Igenomix, Paterna, Spain; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
| | - Aaron J Hsueh
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
| | - Antonio Pellicer
- IVI Foundation, Valencia, Spain; Reproductive Medicine Research Group, Valencia, Spain
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22
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Medrano JV, Andrés MDM, García S, Herraiz S, Vilanova-Pérez T, Goossens E, Pellicer A. Basic and Clinical Approaches for Fertility Preservation and Restoration in Cancer Patients. Trends Biotechnol 2018; 36:199-215. [DOI: 10.1016/j.tibtech.2017.10.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 10/13/2017] [Accepted: 10/18/2017] [Indexed: 12/20/2022]
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23
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Parvari S, Yazdekhasti H, Rajabi Z, Gerayeli Malek V, Rastegar T, Abbasi M. Differentiation of Mouse Ovarian Stem Cells Toward Oocyte-Like Structure by Coculture with Granulosa Cells. Cell Reprogram 2017; 18:419-428. [PMID: 27906587 DOI: 10.1089/cell.2016.0013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
An increasing body of evidence has confirmed existence and function of ovarian stem cells (OSCs). In this study, a novel approach on differentiation of OSCs into oocyte-like cells (OLCs) has been addressed. Recently, different methods have been recruited to isolate and describe aspects of OSCs, but newer and more convenient strategies in isolation are still growing. Herein, a morphology-based method was used to isolate OSCs. Cell suspension of mouse neonatal ovaries was cultured and formed colonies were harvested mechanically and cultivated on mouse embryonic fibroblasts. For differentiation induction, colonies transferred on inactive granulosa cells. Results showed that cells in colonies were positive for alkaline phosphatase activity and reverse transcription-polymerase chain reaction (RT-PCR) confirmed the pluripotency characteristics of cells. Immunofluorescence revealed a positive signal for OCT4, DAZL, MVH, and SSEA1 in colonies as well. Results of RT-PCR and immunofluorescence confirmed that some OLCs were generated within the germ stem cell (GSCs) colonies. The applicability of morphological selection for isolation of GSCs was verified. This method is easier and more economic than other techniques. Our results demonstrate that granulosa cells were effective in inducing the differentiation of OSCs into OLCs through direct cell-to-cell contacts.
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Affiliation(s)
- Soraya Parvari
- 1 Department of Anatomy, Faculty of Medicine, Alborz University of Medical Sciences , Karaj, Iran
| | - Hossein Yazdekhasti
- 2 Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences , Tehran, Iran
| | - Zahra Rajabi
- 2 Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences , Tehran, Iran
| | | | - Tayebeh Rastegar
- 2 Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences , Tehran, Iran
| | - Mehdi Abbasi
- 2 Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences , Tehran, Iran
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24
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Yazdekhasti H, Hosseini MA, Rajabi Z, Parvari S, Salehnia M, Koruji M, Izadyar F, Aliakbari F, Abbasi M. Improved Isolation, Proliferation, and Differentiation Capacity of Mouse Ovarian Putative Stem Cells. Cell Reprogram 2017; 19:132-144. [PMID: 28375748 DOI: 10.1089/cell.2016.0054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The recent discovery of ovarian stem cells in postnatal mammalian ovaries, also referred to as putative stem cells (PSCs), and their roles in mammalian fertility has challenged the long-existing theory that women are endowed with a certain number of germ cells. The rare amount of PSCs is the major limitation for utilizing them through different applications. Therefore, this study was conducted in six phases to find a way to increase the number of Fragilis- and mouse vasa homolog (MVH)-positive sorted cells from 14-day-old NMRI strain mice. Results showed that there is a population of Fragilis- and MVH-positive cells with pluripotent stem cell characteristics, which can be isolated and expanded for months in vitro. PSCs increase their proliferation capacity under the influence of some mitogenic agents, and our results showed that different doses of stem cell factor (SCF) induce PSC proliferation with the maximum increase observed at 50 ng/mL. SCF was also able to increase the number of Fragilis- and MVH-positive cells after sorting by magnetic-activated cell sorting and enhance colony formation efficiency in sorted cells. Differentiation capacity assay indicated that there is a basic level of spontaneous differentiation toward oocyte-like cells during 3 days of culture. However, relative gene expression was significantly higher in the follicle-stimulating hormone-treated groups, especially in the Fragilis- sorted PSCs. We suggest that higher number of PSCs provides us either a greater source of energy that can be injected into energy-impaired oocytes in women with a history of repeat IVF failure or a good source for research.
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Affiliation(s)
- Hossein Yazdekhasti
- 1 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran
| | - Marzieh Agha Hosseini
- 2 Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences , Tehran, Iran
| | - Zahra Rajabi
- 1 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran
| | - Soraya Parvari
- 3 Department of Anatomy, School of Medicine, Alborz University of Medical Sciences , Karaj, Iran
| | - Mojdeh Salehnia
- 4 Department of Anatomy, School of Medical Sciences, Tarbiat Modarres University , Tehran, Iran
| | - Morteza Koruji
- 5 Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences , Tehran, Iran
| | | | - Fereshte Aliakbari
- 1 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran
| | - Mehdi Abbasi
- 1 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran
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25
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Bhartiya D, Patel H. Ovarian stem cells-resolving controversies. J Assist Reprod Genet 2017; 35:393-398. [PMID: 29128912 DOI: 10.1007/s10815-017-1080-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 11/01/2017] [Indexed: 12/13/2022] Open
Abstract
A recent review on ovarian stem cells by Horan and Williams entitled "Oocyte Stem Cells: Fact or Fantasy?" suggests that the debate on ovarian stem cells (OSCs) is still not over. They did not even discuss the presence of two distinct populations of stem cells in the ovary in their review. OSCs are located in the ovary surface epithelium and Tilly's group reported them in the size range of 5-8 μm whereas Virant-Klun's group has reported pluripotent, 2-4 μm OSCs. Our group reported OSCs of two distinct sizes including pluripotent very small embryonic-like stem cells (VSELs) which are smaller in size than RBCs (similar to those reported by Virant-Klun's group) and slightly bigger (similar to those reported by Tilly's group) tissue committed progenitors (OSCs) that presumably differentiate from VSELs. These stem/progenitor cells express receptors for follicle stimulating hormone (FSH) and are activated by FSH. Our opinion article provides explanation to several open-ended questions raised in the review on OSCs by Horan and Williams. VSELs survive chemotherapy; maintain life-long homeostasis; loss of their function due to a compromised niche results in age-related senescence and presence of overlapping pluripotent markers suggest that they may also be implicated in epithelial ovarian cancers.
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Affiliation(s)
- Deepa Bhartiya
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India.
| | - Hiren Patel
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India
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26
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Abstract
Recently, the existence of a mechanism for neo-oogenesis in the ovaries of adult mammals has generated much controversy within reproductive biology. This mechanism, which proposes that the ovary has cells capable of renewing the follicular reserve, has been described for various species of mammals. The first evidence was found in prosimians and humans. However, these findings were not considered relevant because the predominant dogma for reproductive biology at the time was that of Zuckerman. This dogma states that female mammals are born with finite numbers of oocytes that decline throughout postnatal life. Currently, the concept of neo-oogenesis has gained momentum due to the discovery of cells with mitotic activity in adult ovaries of various mammalian species (mice, humans, rhesus monkeys, domestic animals such as pigs, and wild animals such as bats). Despite these reports, the concept of neo-oogenesis has not been widely accepted by the scientific community, generating much criticism and speculation about its accuracy because it has been impossible to reproduce some evidence. This controversy has led to the creation of two positions: one in favour of neo-oogenesis and the other against it. Various animal models have been used in support of both camps, including both classic laboratory animals and domestic and wild animals. The aim of this review is to critically present the current literature on the subject and to evaluate the arguments pro and contra neo-oogenesis in mammals.
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Horan CJ, Williams SA. Oocyte stem cells: fact or fantasy? Reproduction 2017; 154:R23-R35. [PMID: 28389520 DOI: 10.1530/rep-17-0008] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 03/29/2017] [Accepted: 04/07/2017] [Indexed: 01/08/2023]
Abstract
For many decades, the dogma prevailed that female mammals had a finite pool of oocytes at birth and this was gradually exhausted during a lifetime of reproductive function. However, in 2004, a new era began in the field of female oogenesis. A study was published that appeared to detect oocyte-stem cells capable of generating new eggs within mouse ovaries. This study was highly controversial and the years since this initial finding have produced extensive research and even more extensive debate into their possibility. Unequivocal evidence testifying to the existence of oocyte-stem cells (OSCs) has yet to be produced, meanwhile the spectrum of views from both sides of the debate are wide-ranging and surprisingly passionate. Although recent studies have presented some convincing results that germ cells exist and are capable of creating new oocytes, many questions remain. Are these cells present in humans? Do they exist in physiological conditions in a dormant state? This comprehensive review first examines where and how the dogma of a finite pool was established, how this has been challenged over the years and addresses the most pertinent questions as to the current status of their existence, their role in female fertility, and perhaps most importantly, if they do exist, how can we harness these cells to improve a woman's oocyte reserve and treat conditions such as premature ovarian insufficiency (POI: also known as premature ovarian failure, POF).
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Affiliation(s)
- Corrina J Horan
- Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, United Kingdom
| | - Suzannah A Williams
- Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, United Kingdom
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Vanni VS, Viganò P, Papaleo E, Mangili G, Candiani M, Giorgione V. Advances in improving fertility in women through stem cell-based clinical platforms. Expert Opin Biol Ther 2017; 17:585-593. [PMID: 28351161 DOI: 10.1080/14712598.2017.1305352] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Due to their regenerative ability, stem cells are looked at as a promising tool for improving infertility treatments in women. As the main limiting factor in female fertility is represented by the decrease of ovarian reserve, the main goals of stem cell-based clinical platforms would be to obtain in vitro or in vivo neo-oogenesis. Refractory endometrial factor infertility also represents an obstacle for female reproduction for which stem cells might provide novel treatment strategies. Areas covered: A systematic search of the literature was performed on MEDLINE/PubMed database to identify relevant articles using stem-cell based clinical or research platforms in the field of female infertility. Expert opinion: In vitro oogenesis has not so far developed beyond the stage of oocyte-like cells whose normal progression to mature oocytes and ability to be fertilized was not proved. Extensive epigenetic programming of gamete precursors and the complex interactions between somatic and germ cells required for human oogenesis likely represent the main obstacles in stem-cell-based neo-oogenesis. Also resuming oogenesis in vivo in adulthood still appears a distant hypothesis, as there is still a lack of consensus about the existence and functionality of adult ovarian stem cells.
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Affiliation(s)
- Valeria Stella Vanni
- a Obstetrics and Gynaecology Unit , IRCCS San Raffaele Hospital , Milano , Italy.,b Obstetrics and Gynaecology Unit , Vita-Salute San Raffaele University , Milano , Italy
| | - Paola Viganò
- c Division of Genetics and Cell Biology , IRCCS San Raffaele Hospital , Milano , Italy
| | - Enrico Papaleo
- a Obstetrics and Gynaecology Unit , IRCCS San Raffaele Hospital , Milano , Italy
| | - Giorgia Mangili
- a Obstetrics and Gynaecology Unit , IRCCS San Raffaele Hospital , Milano , Italy
| | - Massimo Candiani
- a Obstetrics and Gynaecology Unit , IRCCS San Raffaele Hospital , Milano , Italy.,b Obstetrics and Gynaecology Unit , Vita-Salute San Raffaele University , Milano , Italy
| | - Veronica Giorgione
- a Obstetrics and Gynaecology Unit , IRCCS San Raffaele Hospital , Milano , Italy.,b Obstetrics and Gynaecology Unit , Vita-Salute San Raffaele University , Milano , Italy
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Kawashima I, Kawamura K. Disorganization of the germ cell pool leads to primary ovarian insufficiency. Reproduction 2017; 153:R205-R213. [PMID: 28289071 DOI: 10.1530/rep-17-0015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 02/10/2017] [Accepted: 03/13/2017] [Indexed: 01/26/2023]
Abstract
The mammalian ovary is an organ that controls female germ cell development, storing them and releasing mature oocytes for transporting to the oviduct. During the fetal stage, female germ cells change from a proliferative state to meiosis before forming follicles with the potential for the growth of surrounding somatic cells. Understanding of molecular and physiological bases of germ cell development in the fetal ovary contributed not only to the elucidation of genetic disorders in primary ovarian insufficiency (POI), but also to the advancement of novel treatments for patients with POI. Accumulating evidence indicates that mutations in NOBOX, DAZL and FIGLAgenes are associated with POI. In addition, cell biology studies revealed the important roles of these genes as essential translational factors for germ cell development. Recent insights into the role of the PI3K (phosphatidylinositol 3-kinase)-Akt signaling pathway in primordial follicle activation allowed the development of a new infertility treatment, IVA (in vitro activation), leading to successful pregnancy/delivery in POI patients. Furthermore, elucidation of genetic dynamics underlying female germ cell development could allow regeneration of oocytes from ES (embryonic stem)/iPS (induced pluripotent stem) cells in mammals. The purpose of this review is to summarize basic findings related to female germ cell development and potential clinical implications, especially focusing on POI etiologies. We also summarize evolving new POI therapies based on IVA as well as oocyte regeneration.
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Affiliation(s)
- Ikko Kawashima
- Department of Advanced Reproductive MedicineSt. Marianna University School of Medicine, Kawasaki City, Kanagawa, Japan
| | - Kazuhiro Kawamura
- Department of Advanced Reproductive MedicineSt. Marianna University School of Medicine, Kawasaki City, Kanagawa, Japan
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Yazdekhasti H, Rajabi Z, Parvari S, Abbasi M. Used protocols for isolation and propagation of ovarian stem cells, different cells with different traits. J Ovarian Res 2016; 9:68. [PMID: 27765047 PMCID: PMC5072317 DOI: 10.1186/s13048-016-0274-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 10/03/2016] [Indexed: 11/10/2022] Open
Abstract
Although existence of ovarian stem cells (OSCs) in mammalian postnatal ovary is still under controversy, however, it has been almost accepted that OSCs are contributing actively to folliculogenesis and neo-oogenesis. Recently, various methods with different efficacies have been employed for OSCs isolation from ovarian tissue, which these methods could be chosen depends on aim of isolation and accessible equipments and materials in lab. Although isolated OSCs from different methods have various traits and characterizations, which might become from their different nature and origin, however these stem cells are promising source for woman infertility treatment or source of energy for women with a history of repeat IVF failure in near future. This review has brought together and summarized currently used protocols for isolation and propagation of OSCs in vitro.
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Affiliation(s)
- Hossein Yazdekhasti
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Rajabi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Soraya Parvari
- Department of Anatomy, Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Mehdi Abbasi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Abstract
CONTEXT A current limitation of assisted reproduction is the number of available female gametes. This Commentary discusses in vitro activation (IVA), a technique that activates dormant ovarian follicles so that these follicles can become mature oocytes for fertilization. There is considerable evidence that mechanical signaling plays an important role in oocyte maturation and survival; manipulation of the mechanical environment is a key component of the IVA process. IVA acts on existing follicles and does not promote neo-oogenesis, which likely contributes little to the primordial follicle pool in the adult. CONCLUSIONS Several women with primary ovarian insufficiency who underwent the IVA procedure have achieved live births. IVA might also be applicable to women with pathological diminished ovarian reserve and those with physiological diminished reserve due to natural aging. Cancer patients with cryopreserved ovarian tissue also might benefit from IVA. Based on future studies, IVA could prove to be a revolutionary tool for assisted reproduction.
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Affiliation(s)
- Ophelia Yin
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
| | - Kamaria Cayton
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
| | - James H Segars
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
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32
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Bhartiya D, Shaikh A, Anand S, Patel H, Kapoor S, Sriraman K, Parte S, Unni S. Endogenous, very small embryonic-like stem cells: critical review, therapeutic potential and a look ahead. Hum Reprod Update 2016; 23:41-76. [PMID: 27614362 DOI: 10.1093/humupd/dmw030] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/27/2016] [Accepted: 08/04/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Both pluripotent very small embryonic-like stem cells (VSELs) and induced pluripotent stem (iPS) cells were reported in 2006. In 2012, a Nobel Prize was awarded for iPS technology whereas even today the very existence of VSELs is not well accepted. The underlying reason is that VSELs exist in low numbers, remain dormant under homeostatic conditions, are very small in size and do not pellet down at 250-280g. The VSELs maintain life-long tissue homeostasis, serve as a backup pool for adult stem cells and are mobilized under stress conditions. An imbalance in VSELs function (uncontrolled proliferation) may result in cancer. SEARCH METHODS The electronic database 'Medline/Pubmed' was systematically searched with the subject heading term 'very small embryonic-like stem cells'. OBJECTIVE AND RATIONALE The most primitive stem cells that undergo asymmetric cell divisions to self-renew and give rise to progenitors still remain elusive in the hematopoietic system and testes, while the presence of stem cells in ovary is still being debated. We propose to review the available literature on VSELs, the methods of their isolation and characterization, their ontogeny, how they compare with embryonic stem (ES) cells, primordial germ cells (PGCs) and iPS cells, and their role in maintaining tissue homeostasis. The review includes a look ahead on how VSELs will result in paradigm shifts in basic reproductive biology. OUTCOMES Adult tissue-specific stem cells including hematopoietic, spermatogonial, ovarian and mesenchymal stem cells have good proliferation potential and are indeed committed progenitors (with cytoplasmic OCT-4), which arise by asymmetric cell divisions of pluripotent VSELs (with nuclear OCT-4). VSELs are the most primitive stem cells and postulated to be an overlapping population with the PGCs. Rather than migrating only to the gonads, PGCs migrate and survive in various adult body organs throughout life as VSELs. VSELs express both pluripotent and PGC-specific markers and are epigenetically and developmentally more mature compared with ES cells obtained from the inner cell mass of a blastocyst-stage embryo. As a result, VSELs readily differentiate into three embryonic germ layers and spontaneously give rise to both sperm and oocytes in vitro. Like PGCs, VSELs do not divide readily in culture, nor produce teratoma or integrate in the developing embryo. But this property of being relatively quiescent allows endogenous VSELs to survive various kinds of toxic insults. VSELs that survive oncotherapy can be targeted to induce endogenous regeneration of non-functional gonads. Transplanting healthy niche (mesenchymal) cells have resulted in improved gonadal function and live births. WIDER IMPLICATIONS Being quiescent, VSELs possibly do not accumulate genomic (nuclear or mitochondrial) mutations and thus may be ideal endogenous, pluripotent stem cell candidates for regenerative and reproductive medicine. The presence of VSELs in adult gonads and the fact that they survive oncotherapy may obviate the need to bank gonadal tissue for fertility preservation prior to oncotherapy. VSELs and their ability to undergo spermatogenesis/neo-oogenesis in the presence of a healthy niche will help identify newer strategies toward fertility restoration in cancer survivors, delaying menopause and also enabling aged mothers to have better quality eggs.
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Affiliation(s)
- Deepa Bhartiya
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India
| | - Ambreen Shaikh
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India
| | - Sandhya Anand
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India
| | - Hiren Patel
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India
| | - Sona Kapoor
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India
| | - Kalpana Sriraman
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India.,The Foundation for Medical Research, 84-A, RG Thadani Marg, Worli, Mumbai 400018, India
| | - Seema Parte
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India.,Department of Physiology, James Graham Brown Cancer Centre, University of Louisville School of Medicine, 2301 S 3rd St, Louisville, KY 40202, USA
| | - Sreepoorna Unni
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (Indian Council of Medical Research), Jehangir Merwanji Street, Parel, Mumbai 400 012, India.,Inter Disciplinary Studies Department, University College, Zayed University, Academic City, PO Box 19282, Dubai, United Arab Emirates
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Abstract
The derivation of human embryonic stem (hES) cells heralds a new era in stem cell research, generating excitement for their therapeutic potential in regenerative medicine. Pioneering work of embryologists, developmental biologists, and reproductive medicine practitioners in in vitro fertilization clinics has facilitated hES cell research. This review summarizes current research focused on optimizing hES cell culture conditions for good manufacturing practice, directing hES cell differentiation toward trophectoderm and germ cells, and approaches used to reprogram cells for pluripotent cell derivation. The identification of germ stem cells in the testis and the recent controversy over their existence in the ovary raise the possibility of harnessing them for treating young cancer survivors. There is also the potential to harvest fetal stem cells with pluripotent cell-like properties from discarded placental tissues. The recent identification of adult stem/progenitor cell activity in the human endometrium offers a new understanding of common gynecological diseases. Discoveries resulting from research into embryonic, germ, fetal, and adult stem cells are highly relevant to human reproduction.
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Affiliation(s)
- Caroline E Gargett
- Centre for Women's Health Research, Monash Institute of Medical Research, and Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton, Victoria, Australia.
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34
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Ding X, Liu G, Xu B, Wu C, Hui N, Ni X, Wang J, Du M, Teng X, Wu J. Human GV oocytes generated by mitotically active germ cells obtained from follicular aspirates. Sci Rep 2016; 6:28218. [PMID: 27357640 PMCID: PMC4928061 DOI: 10.1038/srep28218] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 06/01/2016] [Indexed: 01/26/2023] Open
Abstract
Human female germline stem cells (FGSCs) have opened new opportunities for understanding human oogenesis, delaying menopause, treating infertility, and providing a new strategy for preserving fertility. However, the shortage of adult human ovaries tissues available impedes their future investigations and clinical applications. Here, we have established FGSC lines from scarce ovarian cortical tissues that exist in follicular aspirates (faFGSCs), which are produced and discarded in in vitro fertilization centers worldwide. The faFGSCs have characteristics of germline stem cells involved in the gene expression profile, growth characteristics, and a normal karyotype consistent with that of FGSCs obtained from ovarian cortexes surgically removed from patients (srFGSCs). Furthermore, faFGSCs have developmental potentials including spontaneous differentiation into oocytes under feeder-free conditions, communicating with granulosa cells by gap junctions and paracrine factors, entering meiosis after RA induction, as well as forming follicles after injection into human ovarian cortical tissues xenografted into adult immunodeficient female mice. Lastly, we developed a strategy guiding FGSCs differentiated into germinal vesicle (GV) stage oocytes in vitro and revealed their developmental mechanisms. Our study not only provides a new approach to obtain human FGSCs for medical treatment, but also opens several avenues to investigate human oogenesis in vitro.
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Affiliation(s)
- Xinbao Ding
- Renji Hospital Shanghai Jiaotong University School of Medicine, Key Laboratory for the Genetics of Developmental &Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Guishu Liu
- The First People's Hospital of Chenzhou, Chenzhou 42300, Hunan, China
| | - Bo Xu
- Renji Hospital Shanghai Jiaotong University School of Medicine, Key Laboratory for the Genetics of Developmental &Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Changqing Wu
- Renji Hospital Shanghai Jiaotong University School of Medicine, Key Laboratory for the Genetics of Developmental &Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ning Hui
- Changhai Hospital of Second Military Medical University, Shanghai 200433, China
| | - Xin Ni
- Department of Physiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Jian Wang
- Renji Hospital Shanghai Jiaotong University School of Medicine, Key Laboratory for the Genetics of Developmental &Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Meirong Du
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Xiaoming Teng
- Center of Reproductive medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, China
| | - Ji Wu
- Renji Hospital Shanghai Jiaotong University School of Medicine, Key Laboratory for the Genetics of Developmental &Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China.,Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750004, China.,Shanghai Key Laboratory of Reproductive Medicine, Shanghai 200025, China
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35
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FACS-sorted putative oogonial stem cells from the ovary are neither DDX4-positive nor germ cells. Sci Rep 2016; 6:27991. [PMID: 27301892 PMCID: PMC4908409 DOI: 10.1038/srep27991] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/26/2016] [Indexed: 12/11/2022] Open
Abstract
Whether the adult mammalian ovary contains oogonial stem cells (OSCs) is controversial. They have been isolated by a live-cell sorting method using the germ cell marker DDX4, which has previously been assumed to be cytoplasmic, not surface-bound. Furthermore their stem cell and germ cell characteristics remain disputed. Here we show that although OSC-like cells can be isolated from the ovary using an antibody to DDX4, there is no good in silico modelling to support the existence of a surface-bound DDX4. Furthermore these cells when isolated were not expressing DDX4, and did not initially possess germline identity. Despite these unremarkable beginnings, they acquired some pre-meiotic markers in culture, including DDX4, but critically never expressed oocyte-specific markers, and furthermore were not immortal but died after a few months. Our results suggest that freshly isolated OSCs are not germ stem cells, and are not being isolated by their DDX4 expression. However it may be that culture induces some pre-meiotic markers. In summary the present study offers weight to the dogma that the adult ovary is populated by a fixed number of oocytes and that adult de novo production is a rare or insignificant event.
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36
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37
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Jung D, Kee K. Insights into female germ cell biology: from in vivo development to in vitro derivations. Asian J Androl 2016; 17:415-20. [PMID: 25652637 PMCID: PMC4430939 DOI: 10.4103/1008-682x.148077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Understanding the mechanisms of human germ cell biology is important for developing infertility treatments. However, little is known about the mechanisms that regulate human gametogenesis due to the difficulties in collecting samples, especially germ cells during fetal development. In contrast to the mitotic arrest of spermatogonia stem cells in the fetal testis, female germ cells proceed into meiosis and began folliculogenesis in fetal ovaries. Regulations of these developmental events, including the initiation of meiosis and the endowment of primordial follicles, remain an enigma. Studying the molecular mechanisms of female germ cell biology in the human ovary has been mostly limited to spatiotemporal characterizations of genes or proteins. Recent efforts in utilizing in vitro differentiation system of stem cells to derive germ cells have allowed researchers to begin studying molecular mechanisms during human germ cell development. Meanwhile, the possibility of isolating female germline stem cells in adult ovaries also excites researchers and generates many debates. This review will mainly focus on presenting and discussing recent in vivo and in vitro studies on female germ cell biology in human. The topics will highlight the progress made in understanding the three main stages of germ cell developments: namely, primordial germ cell formation, meiotic initiation, and folliculogenesis.
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Affiliation(s)
| | - Kehkooi Kee
- Department of Basic Medical Sciences, Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
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38
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Abstract
Stem cells have great value in clinical application because of their ability to self-renew and their potential to differentiate into many different cell types. Mammalian gonads, including testes for males and ovaries for females, are composed of germline and somatic cells. In male mammals, spermatogonial stem cells maintain spermatogenesis which occurs continuously in adult testis. Likewise, a growing body of evidence demonstrated that female germline stem cells could be found in mammalian ovaries. Meanwhile, prior studies have shown that somatic stem cells exist in both testes and ovaries. In this chapter, we focus on mammalian gonad stem cells and discuss their characteristics as well as differentiation potentials.
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Affiliation(s)
- Ji Wu
- Key Laboratory for the Genetics of Developmental & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, No. 800. Dongchuan Road, Minhang District, Shanghai, 200240, China.
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai, 200025, China.
| | - Xinbao Ding
- Key Laboratory for the Genetics of Developmental & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, No. 800. Dongchuan Road, Minhang District, Shanghai, 200240, China
| | - Jian Wang
- Key Laboratory for the Genetics of Developmental & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, No. 800. Dongchuan Road, Minhang District, Shanghai, 200240, China
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39
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El-Hayek S, Clarke HJ. Control of Oocyte Growth and Development by Intercellular Communication Within the Follicular Niche. Results Probl Cell Differ 2016; 58:191-224. [PMID: 27300180 DOI: 10.1007/978-3-319-31973-5_8] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the mammalian ovary, each oocyte grows and develops within its own structural and developmental niche-the follicle. Together with the female germ cell in the follicle are somatic granulosa cells, specialized companion cells that surround the oocyte and provide support to it, and an outer layer of thecal cells that serve crucial roles including steroid synthesis. These follicular compartments function as a single physiological unit whose purpose is to produce a healthy egg, which upon ovulation can be fertilized and give rise to a healthy embryo, thus enabling the female germ cell to fulfill its reproductive potential. Beginning from the initial stage of follicle formation and until terminal differentiation at ovulation, oocyte and follicle growth depend absolutely on cooperation between the different cellular compartments. This cooperation synchronizes the initiation of oocyte growth with follicle activation. During growth, it enables metabolic support for the follicle-enclosed oocyte and allows the follicle to fulfill its steroidogenic potential. Near the end of the growth period, intra-follicular interactions prevent the precocious meiotic resumption of the oocyte and ensure its nuclear differentiation. Finally, cooperation enables the events of ovulation, including meiotic maturation of the oocyte and expansion of the cumulus granulosa cells. In this chapter, we discuss the cellular interactions that enable the growing follicle to produce a healthy oocyte, focusing on the communication between the germ cell and the surrounding granulosa cells.
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Affiliation(s)
- Stephany El-Hayek
- Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada
- Department of Biology, McGill University, Montreal, QC, Canada
- Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Block E-M0.2218, Montreal, QC, Canada, H4A 3J1
| | - Hugh J Clarke
- Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada.
- Department of Biology, McGill University, Montreal, QC, Canada.
- Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Block E-M0.2218, Montreal, QC, Canada, H4A 3J1.
- Department of Experimental Medicine, McGill University, Montreal, QC, Canada.
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40
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The Controversy, Challenges, and Potential Benefits of Putative Female Germline Stem Cells Research in Mammals. Stem Cells Int 2015; 2016:1728278. [PMID: 26788065 PMCID: PMC4693009 DOI: 10.1155/2016/1728278] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 08/04/2015] [Accepted: 08/11/2015] [Indexed: 11/30/2022] Open
Abstract
The conventional view is that female mammals lose their ability to generate new germ cells after birth. However, in recent years, researchers have successfully isolated and cultured a type of germ cell from postnatal ovaries in a variety of mammalian species that have the abilities of self-proliferation and differentiation into oocytes, and this finding indicates that putative germline stem cells maybe exist in the postnatal mammalian ovaries. Herein, we review the research history and discovery of putative female germline stem cells, the concept that putative germline stem cells exist in the postnatal mammalian ovary, and the research progress, challenge, and application of putative germline stem cells in recent years.
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41
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Abstract
The adult mammalian ovary is devoid of definitive germline stem cells. As such, female reproductive senescence largely results from the depletion of a finite ovarian follicle pool that is produced during embryonic development. Remarkably, the crucial nature and regulation of follicle assembly and survival during embryogenesis is just coming into focus. This developmental pathway involves the coordination of meiotic progression and the breakdown of germ cell cysts into individual oocytes housed within primordial follicles. Recent evidence also indicates that genetic and environmental factors can specifically perturb primordial follicle assembly. Here, we review the cellular and molecular mechanisms by which the mammalian ovarian reserve is established, highlighting the presence of a crucial checkpoint that allows survival of only the highest-quality oocytes.
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Affiliation(s)
- Kathryn J Grive
- Brown University, MCB Graduate Program, Providence, RI 02912, USA
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Vassena R, Eguizabal C, Heindryckx B, Sermon K, Simon C, van Pelt AMM, Veiga A, Zambelli F. Stem cells in reproductive medicine: ready for the patient? Hum Reprod 2015. [PMID: 26202914 DOI: 10.1093/humrep/dev181] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
STUDY QUESTION Are there effective and clinically validated stem cell-based therapies for reproductive diseases? SUMMARY ANSWER At the moment, clinically validated stem cell treatments for reproductive diseases and alterations are not available. WHAT IS KNOWN ALREADY Research in stem cells and regenerative medicine is growing in scope, and its translation to the clinic is heralded by the recent initiation of controlled clinical trials with pluripotent derived cells. Unfortunately, stem cell 'treatments' are currently offered to patients outside of the controlled framework of scientifically sound research and regulated clinical trials. Both physicians and patients in reproductive medicine are often unsure about stem cells therapeutic options. STUDY DESIGN, SIZE, DURATION An international working group was assembled to review critically the available scientific literature in both the human species and animal models. PARTICIPANTS/MATERIALS, SETTING, METHODS This review includes work published in English until December 2014, and available through Pubmed. MAIN RESULTS AND THE ROLE OF CHANCE A few areas of research in stem cell and reproductive medicine were identified: in vitro gamete production, endometrial regeneration, erectile dysfunction amelioration, vaginal reconstruction. The stem cells studied range from pluripotent (embryonic stem cells and induced pluripotent stem cells) to monopotent stem cells, such as spermatogonial stem cells or mesenchymal stem cells. The vast majority of studies have been carried out in animal models, with data that are preliminary at best. LIMITATIONS, REASONS FOR CAUTION This review was not conducted in a systematic fashion, and reports in publications not indexed in Pubmed were not analyzed. WIDER IMPLICATIONS OF THE FINDINGS A much broader clinical knowledge will have to be acquired before translation to the clinic of stem cell therapies in reproductive medicine; patients and physicians should be wary of unfounded claims of improvement of existing medical conditions; at the moment, effective stem cell treatment for reproductive diseases and alterations is not available. STUDY FUNDING/COMPETING INTERESTS None. TRIAL REGISTRATION NUMBER NA.
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Affiliation(s)
| | - C Eguizabal
- Cell Therapy and Stem Cell Laboratory, Basque Center for Transfusion and Human Tissues, Galdakao, Spain
| | - B Heindryckx
- Ghent-Fertility and Stem Cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium
| | - K Sermon
- Research Group Reproduction and Genetics, Vrije Universtiteit Brussel (VUB), Brussels, Belgium
| | - C Simon
- Fundación Instituto Valenciano de Infertilidad (FIVI), and Department of Pediatrics, Obstetrics & Gynecology, Valencia University & INCLIVA, Valencia, Spain Department of Obstetrics and Gynecology, School of Medicine, Stanford University, Stanford, CA, USA
| | - A M M van Pelt
- Center for Reproductive Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - A Veiga
- Reproductive Medicine Service, Hospital Universitari Quiron Dexeus, Barcelona, Spain Stem Cell Bank, Centre for Regenerative Medicine of Barcelona, Barcelona, Spain
| | - F Zambelli
- Research Group Reproduction and Genetics, Vrije Universtiteit Brussel (VUB), Brussels, Belgium S.I.S.Me.R. Reproductive Medicine Unit, Bologna, Italy
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43
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Moreno I, Míguez-Forjan JM, Simón C. Artificial gametes from stem cells. Clin Exp Reprod Med 2015; 42:33-44. [PMID: 26161331 PMCID: PMC4496429 DOI: 10.5653/cerm.2015.42.2.33] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 06/18/2015] [Accepted: 06/18/2015] [Indexed: 11/06/2022] Open
Abstract
The generation of artificial gametes is a real challenge for the scientific community today. In vitro development of human eggs and sperm will pave the way for the understanding of the complex process of human gametogenesis and will provide with human gametes for the study of infertility and the onset of some inherited disorders. However, the great promise of artificial gametes resides in their future application on reproductive treatments for all these people wishing to have genetically related children and for which gamete donation is now their unique option of parenthood. This is the case of infertile patients devoid of suitable gametes, same sex couples, singles and those fertile couples in a high risk of transmitting serious diseases to their progeny. In the search of the best method to obtain artificial gametes, many researchers have successfully obtained human germ cell-like cells from stem cells at different stages of differentiation. In the near future, this field will evolve to new methods providing not only viable but also functional and safe artificial germ cells. These artificial sperm and eggs should be able to recapitulate all the genetic and epigenetic processes needed for the correct gametogenesis, fertilization and embryogenesis leading to the birth of a healthy and fertile newborn.
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Affiliation(s)
- Inmaculada Moreno
- Department of Research and Development, Igenomix S.L., Paternam, Spain
| | | | - Carlos Simón
- Department of Research and Development, Igenomix S.L., Paternam, Spain. ; Fundación Instituto Valenciano de Infertilidad (FIVI), Valencia, Spain. ; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
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Parvari S, Abbasi M, Abbasi N, Malek VG, Amidi F, Aval FS, Roudkenar MH, Izadyar F. Stem cell isolation by a morphology-based selection method in postnatal mouse ovary. Arch Med Sci 2015; 11:670-8. [PMID: 26170863 PMCID: PMC4495162 DOI: 10.5114/aoms.2015.52374] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 04/23/2013] [Accepted: 07/29/2013] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION An increasing body of evidence has emerged regarding the existence and function of spermatogonial stem cells (SSCs); however, their female counterparts are the subject of extensive debate. Theoretically, ovarian germ stem cells (GSCs) have to reside in the murine ovary to support and replenish the follicle pool during the reproductive life span. Recently, various methods have been recruited to isolate and describe aspects of ovarian GSCs, but newer and more convenient strategies in isolation are still growing. Herein, a morphology-based method was used to isolate GSCs. MATERIAL AND METHODS A cell suspension of mouse neonatal ovaries was cultured. Colonies of GSCs were harvested mechanically and cultivated on mouse embryonic fibroblasts (MEF). Alkaline phosphatase activity was assessed to verify stemness features of cells in colonies. Expression of germ and stem cell specific genes (Oct-4, Nanog, Fragilis, C-kit, Dazl, and Mvh) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Immunofluorescence of Oct4, Dazl, Mvh, and SSEA-1 was also performed. RESULTS Small colonies without a clear border appeared during the first 4 days of culture, and the size of colonies increased rapidly. Cells in colonies were positive for alkaline phosphatase activity. Reverse transcription-polymerase chain reaction showed that Oct-4, Fragilis, C-kit, Nanog, Mvh, and Dazl were expressed in colony-forming cells. Immunofluorescence revealed a positive signal for Oct4, Dazl, Mvh, and SSEA-1 in colonies as well. CONCLUSIONS The applicability of morphological selection for isolation of GSCs was verified. This method is easier and more economical than other techniques. The availability of ovarian stem cells can motivate further studies in development of oocyte and cell-based therapies.
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Affiliation(s)
- Soraya Parvari
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Abbasi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloufar Abbasi
- Faculty of Medicine, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | | | - Fardin Amidi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Ozakpinar OB, Maurer AM, Ozsavci D. Ovarian stem cells: From basic to clinical applications. World J Stem Cells 2015; 7:757-768. [PMID: 26029346 PMCID: PMC4444615 DOI: 10.4252/wjsc.v7.i4.757] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 01/28/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The field of reproductive biology has undergone significant developments in the last decade. The notion that there is a fixed reserve pool of oocytes before birth was established by Zuckerman in 1951. However, in 2004, an article published in nature challenged this central dogma of mammalian reproductive biology. Tilly’s group reported the existence of ovarian germline stem cells (GSCs) in postnatal ovaries of mice and suggested that the bone marrow could be an extragonadal source of ovarian GSCs. These findings were strongly criticized; however, several independent groups have since successfully isolated and characterized ovarian GSCs in postnatal mice. The ovarian GSCs are located in the ovarian surface epithelium and express markers of undifferentiated GSCs. When transplanted into mouse ovaries, mouse ovarian GSCs could differentiate and produce embryos and offspring. Similarly, in a recent study, ovarian GSCs were found to be present in the ovaries of women of reproductive age. Conversely, there is increasing evidence that stem cells responsible for maintaining a healthy state in normal tissue may be a source of some cancers, including ovarian cancer. Cancer stem cells (CSCs) have been found in many tissues, including ovaries. Some researchers have suggested that ovarian cancer may be a result of the transformation and dysfunction of ovarian GSCs with self-renewal properties. Drug resistant and metastasis-generating CSCs are responsible for many important problems affecting ovarian cancer patients. Therefore, the identification of CSCs will provide opportunities for the development of new therapeutic strategies for treatments for infertility and ovarian cancer. In this article, we summarize the current understanding of ovarian GSCs in adult mammals, and we also discuss whether there is a relationship between GSCs and CSCs.
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46
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Cheng Y, Xie N, Jin P, Wang T. DNA methylation and hydroxymethylation in stem cells. Cell Biochem Funct 2015; 33:161-73. [PMID: 25776144 DOI: 10.1002/cbf.3101] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 02/17/2015] [Accepted: 02/24/2015] [Indexed: 12/18/2022]
Abstract
In mammals, DNA methylation and hydroxymethylation are specific epigenetic mechanisms that can contribute to the regulation of gene expression and cellular functions. DNA methylation is important for the function of embryonic stem cells and adult stem cells (such as haematopoietic stem cells, neural stem cells and germline stem cells), and changes in DNA methylation patterns are essential for successful nuclear reprogramming. In the past several years, the rediscovery of hydroxymethylation and the TET enzymes expanded our insights tremendously and uncovered more dynamic aspects of cytosine methylation regulation. Here, we review the current knowledge and highlight the most recent advances in DNA methylation and hydroxymethylation in embryonic stem cells, induced pluripotent stem cells and several well-studied adult stems cells. Our current understanding of stem cell epigenetics and new advances in the field will undoubtedly stimulate further clinical applications of regenerative medicine in the future.
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Affiliation(s)
- Ying Cheng
- Department of Human Genetics, Emory University, Atlanta, GA, USA
| | - Nina Xie
- Department of Human Genetics, Emory University, Atlanta, GA, USA.,Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Peng Jin
- Department of Human Genetics, Emory University, Atlanta, GA, USA
| | - Tao Wang
- Cardiovascular Research Institute and Department of Physiology, University of California, San Francisco, CA, USA
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Hummitzsch K, Anderson RA, Wilhelm D, Wu J, Telfer EE, Russell DL, Robertson SA, Rodgers RJ. Stem cells, progenitor cells, and lineage decisions in the ovary. Endocr Rev 2015; 36:65-91. [PMID: 25541635 PMCID: PMC4496428 DOI: 10.1210/er.2014-1079] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 12/15/2014] [Indexed: 01/05/2023]
Abstract
Exploring stem cells in the mammalian ovary has unleashed a Pandora's box of new insights and questions. Recent evidence supports the existence of stem cells of a number of the different cell types within the ovary. The evidence for a stem cell model producing mural granulosa cells and cumulus cells is strong, despite a limited number of reports. The recent identification of a precursor granulosa cell, the gonadal ridge epithelial-like cell, is exciting and novel. The identification of female germline (oogonial) stem cells is still very new and is currently limited to just a few species. Their origins and physiological roles, if any, are unknown, and their potential to produce oocytes and contribute to follicle formation in vivo lacks robust evidence. The precursor of thecal cells remains elusive, and more compelling data are needed. Similarly, claims of very small embryonic-like cells are also preliminary. Surface epithelial cells originating from gonadal ridge epithelial-like cells and from the mesonephric epithelium at the hilum of the ovary have also been proposed. Another important issue is the role of the stroma in guiding the formation of the ovary, ovigerous cords, follicles, and surface epithelium. Immune cells may also play key roles in developmental patterning, given their critical roles in corpora lutea formation and regression. Thus, while the cellular biology of the ovary is extremely important for its major endocrine and fertility roles, there is much still to be discovered. This review draws together the current evidence and perspectives on this topic.
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Affiliation(s)
- Katja Hummitzsch
- Discipline of Obstetrics and Gynaecology (K.H., D.L.R., S.A.R., R.J.R.), School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia 5005; Medical Research Council Centre for Reproductive Health (R.A.A.), The University of Edinburgh, The Queens Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; Department of Anatomy and Developmental Biology (D.W.), Monash University, Clayton, Victoria, Australia 3800; Bio-X Institutes (J.W.), Shanghai Jiao Tong University, Shanghai 200240, China; and Institute of Cell Biology and Centre for Integrative Physiology (E.E.T), The University of Edinburgh, Edinburgh EH8 9XE, United Kingdom
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Hendriks S, Dancet EA, van Pelt AM, Hamer G, Repping S. Artificial gametes: a systematic review of biological progress towards clinical application. Hum Reprod Update 2015; 21:285-96. [DOI: 10.1093/humupd/dmv001] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 12/29/2014] [Indexed: 01/15/2023] Open
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Zhang H, Liu L, Li X, Busayavalasa K, Shen Y, Hovatta O, Gustafsson JÅ, Liu K. Life-long in vivo cell-lineage tracing shows that no oogenesis originates from putative germline stem cells in adult mice. Proc Natl Acad Sci U S A 2014; 111:17983-17988. [PMID: 25453063 PMCID: PMC4273382 DOI: 10.1073/pnas.1421047111] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Whether or not oocyte regeneration occurs in adult life has been the subject of much debate. In this study, we have traced germ-cell lineages over the life spans of three genetically modified mouse models and provide direct evidence that oogenesis does not originate from any germline stem cells (GSCs) in adult mice. By selective ablation of all existing oocytes in a Gdf9-Cre;iDTR mouse model, we have demonstrated that no new germ cells were ever regenerated under pathological conditions. By in vivo tracing of oocytes and follicles in the Sohlh1-CreER(T2);R26R and Foxl2-CreER(T2);mT/mG mouse models, respectively, we have shown that the initial pool of oocytes is the only source of germ cells throughout the life span of the mice and that no adult oogenesis ever occurs under physiological conditions. Our findings clearly show that there are no GSCs that contribute to adult oogenesis in mice and that the initial pool of oocytes formed in early life is the only source of germ cells throughout the entire reproductive life span.
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Affiliation(s)
- Hua Zhang
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, Sweden
| | - Lian Liu
- Cancer Center, Qilu Hospital of Shandong University, 250012 Shandong, China
| | - Xin Li
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, Sweden
| | - Kiran Busayavalasa
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, Sweden
| | - Yan Shen
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, Sweden
| | - Outi Hovatta
- Division of Obstetrics and Gynecology, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute and Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden; and
| | - Jan-Åke Gustafsson
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204
| | - Kui Liu
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, Sweden;
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Ishii T. Human iPS Cell-Derived Germ Cells: Current Status and Clinical Potential. J Clin Med 2014; 3:1064-83. [PMID: 26237592 PMCID: PMC4470171 DOI: 10.3390/jcm3041064] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 09/17/2014] [Accepted: 09/22/2014] [Indexed: 01/15/2023] Open
Abstract
Recently, fertile spermatozoa and oocytes were generated from mouse induced pluripotent (iPS) cells using a combined in vitro and in vivo induction system. With regard to germ cell induction from human iPS cells, progress has been made particularly in the male germline, demonstrating in vitro generation of haploid, round spermatids. Although iPS-derived germ cells are expected to be developed to yield a form of assisted reproductive technology (ART) that can address unmet reproductive needs, genetic and/or epigenetic instabilities abound in iPS cell generation and germ cell induction. In addition, there is still room to improve the induction protocol in the female germline. However, rapid advances in stem cell research are likely to make such obstacles surmountable, potentially translating induced germ cells into the clinical setting in the immediate future. This review examines the current status of the induction of germ cells from human iPS cells and discusses the clinical potential, as well as future directions.
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Affiliation(s)
- Tetsuya Ishii
- Office of Health and Safety, Hokkaido University, Sapporo 060-0808, Japan.
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