scholarly journals Oogonial stem cells as a model to study age-associated infertility in women

2015 ◽  
Vol 27 (6) ◽  
pp. 969 ◽  
Author(s):  
Neha Garg ◽  
David A. Sinclair
Keyword(s):  
Stem Cells ◽  
Ovarian Function ◽  
Biological Process ◽  
Reproductive Aging ◽  
Germline Stem Cells ◽  
Female Age ◽  
Ovarian Aging ◽  
Age Related ◽  
Fixed Pool

Fertility is the first biological process to break down during aging, thereby making it a useful tool to understand fundamental processes of aging. Reproductive aging in females is associated with a loss of ovarian function characterised by a reduction in the number and quality of oocytes. The central dogma, namely that females are born with a fixed pool of oocytes that progressively decline with increasing maternal age, has been challenged by evidence supporting postnatal oogenesis in mammals. Reports demonstrating formation of new oocytes from newly discovered germline stem cells, referred to as oogonial stem cells (OSCs), has opened new avenues for treatment of female infertility. In this review we discuss why the OSCs possibly lose their regenerative potential over time, and focus specifically on the aging process in germline stem cells as a possible mechanism for understanding female age-related infertility and how we can slow or delay ovarian aging.

Stem Cell Transplantation Improves Ovarian Function through Paracrine Mechanisms

2020 ◽  
Vol 20 (5) ◽  
pp. 347-355
Author(s):  
Wenlin Jiao ◽  
Xin Mi ◽  
Yingying Qin ◽  
Shidou Zhao
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Ovarian Aging ◽  
Age Related

The ovary serves as the source of oocytes for the maintenance of female fertility and is a major supplier of sex hormones for endocrine homeostasis. Various circumstances such as genetic defects, autoimmune disorders, natural aging and environmental toxins can damage the ovaries leading to diminished ovarian function, and there are currently no effective treatment regimens for such loss of function. Stem cells show promise for treating many refractory diseases, and stem cell transplantation has been shown to be effective and safe as a new therapeutic method for ovarian injuries and ovarian aging in both animal models and women with premature ovarian insufficiency. However, the specific mechanisms that underlie the observed positive outcomes of improving ovarian function are not well understood. Evidence is mounting that stem cell-derived conditioned medium, exosomes, and trophic growth factors can also inhibit ovarian damage and alleviate the age-related fertility decline in female mice, indicating that stem cells exert the paracrine effects. Further studies to elucidate the cellular and molecular mechanisms, including signaling pathways, for improving ovarian function and promoting the secretory capacity of stem cells will fill the bench-to-bedside gap of stem cell therapy in the clinic. Furthermore, in-depth analyses of the stem cell secretome and identification of the key effective components will underlie a new paradigm in cell-free therapeutic strategies for ovarian insufficiency and ovarian aging.

scholarly journals YAP/Yorkie in the germline modulates the age-related decline of germline stem cells and niche cells

PLoS ONE ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. e0213327 ◽  
Author(s):  
Deepthy Francis ◽  
Bhavna Chanana ◽  
Beatriz Fernandez ◽  
Benjamin Gordon ◽  
Tiffany Mak ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germline Stem Cells ◽  
Age Related

scholarly journals Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT

2020 ◽  
Vol 245 (8) ◽  
pp. 711-719
Author(s):  
Min Jung Park ◽  
Jun-Woo Ahn ◽  
Ki Hyung Kim ◽  
Junghee Bang ◽  
Seung Chul Kim ◽  
...  
Keyword(s):  
Embryo Development ◽  
Ovarian Function ◽  
Antral Follicle ◽  
Antral Follicle Count ◽  
Development Rate ◽  
Ovarian Aging ◽  
Age Related ◽  
Morphogenetic Protein ◽  
New Information ◽  
Potential Biomarkers

This study investigated ovarian expressions of bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), and C-KIT according to age in female mice to determine whether these factors can be served as new potential biomarkers of ovarian aging. Ovaries were collected from mice aged 10, 20, 30, and 40 weeks, and ovarian expressions of BMP15, GDF9, and C-KIT were examined by real-time PCR, Western blot, and immunohistochemistry. Follicle counts were measured on histological hematoxylin and eosin staining. In the second experiment to evaluate ovarian function, after superovulation with PMSG and hCG, the numbers of zygotes retrieved and embryo development rate were examined. Ovarian expressions of BMP15, GDF9, and C-KIT decreased with age. Follicle counts, numbers of retrieved zygotes, and embryo development rate were also significantly reduced in old mice over 30 weeks compared with young mice. These results indicate that these factors could be served as new potential biomarkers of ovarian aging. Impact statement Ovarian aging is becoming a more important issue in terms of fertility preservation and infertility treatment. Serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC) are being practically used as markers of ovarian aging as well as ovarian reserve in human. However, these factors have some drawbacks in assessing ovarian aging and reserve. Therefore, the identification of ovarian expressions of BMP15, GDF9, and C-KIT according to female could be applied as a potent predictor of ovarian aging. This work provides new information on the development of diagnosis and treatment strategy of age-related fertility decline and premature ovarian insufficiency.

scholarly journals Mitochondrial Dysfunction and Ovarian Aging

Endocrinology ◽  
2020 ◽  
Vol 161 (2) ◽  
Author(s):  
Işıl Kasapoğlu ◽  
Emre Seli
Keyword(s):  
Mitochondrial Dysfunction ◽  
Ovarian Reserve ◽  
Reproductive Aging ◽  
Ovarian Dysfunction ◽  
Ongoing Research ◽  
Ovarian Aging ◽  
Age Related ◽  
Age Related Changes

Abstract As women delay childbearing because of demographic and socioeconomic trends, reproductive aging and ensuing ovarian dysfunction become increasingly more prevalent causes of infertility. Age-related decline in fertility is characterized by both quantitative and qualitative deterioration of the ovarian reserve. Importantly, disorders of aging are frequently associated with mitochondrial dysfunction, as are impaired oogenesis and embryogenesis. Ongoing research explores the role of mitochondrial dysfunction in ovarian aging, and potential ways to exploit mitochondrial mechanisms to slow down or reverse age-related changes in female gonads.

scholarly journals Therapeutic Potential of HUMSCs in Female Reproductive Aging

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiaojuan Mei ◽  
Hongbei Mou ◽  
Xuemei Liu ◽  
Wenpei Xiang
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Ovarian Function ◽  
Therapeutic Potential ◽  
Human Umbilical Cord ◽  
Great Success ◽  
Reproductive Aging ◽  
Paracrine Factors ◽  
Paracrine Effects

With the development of regenerative medicine, stem cells are being considered more frequently for the treatment of reproductive aging. Human umbilical cord mesenchymal stem cells have been reported to improve the reserve function of aging ovaries through their homing and paracrine effects. In this process, paracrine factors secreted by stem cells play an important role in ovarian recovery. Although the transplantation of human umbilical cord mesenchymal stem cells to improve ovarian function has been studied with great success in animal models of reproductive aging, their application in clinical research and therapy is still relatively rare. Therefore, this paper reviews the role of human umbilical cord mesenchymal stem cells in the treatment of reproductive aging and their related mechanisms, and it does so in order to provide a theoretical basis for further research and clinical treatment.

268 INFLUENCE OF DONOR AGE ON DEVELOPMENTAL COMPETENCE OF IN VITRO v. IN VIVO MATURED BOVINE OOCYTES OBTAINED BY REPEATED OVUM PICKUP FROM FOLLICLE-STIMULATING-HORMONE-STIMULATED AND NONSTIMULATED ANIMALS

2011 ◽  
Vol 23 (1) ◽  
pp. 232
Author(s):  
M. Matthiesen ◽  
H. D. Reichenbach ◽  
F. A. Habermann ◽  
M. Reichenbach ◽  
G. J. Arnold ◽  
...  
Keyword(s):  
Mixed Model ◽  
Ovarian Function ◽  
Age Groups ◽  
Developmental Competence ◽  
Reproductive Aging ◽  
Donor Age ◽  
Ovarian Aging ◽  
Bovine Oocytes

Recent findings on oogenesis, folliculogenesis, and ovarian aging in cows make the bovine system an attractive model for elucidating ovarian function and dysfunction as well as reproductive aging in women. The aim of the present study was to investigate the influence of donor age on the developmental competence of in vitro v. in vivo matured bovine cumulus–oocyte complexes (COC) obtained by ultrasound-guided repeated ovum pickup (OPU). Two groups (G1 and G2) of German Simmental heifers (14 months old at the beginning of the experiment, n = 5 and n = 7), first-lactation young cows (2–4 y old, n = 5 and n = 3), and old cows (10–15 y old, n = 5 and n = 3) were subjected to twice-weekly OPU without hormonal prestimulation 32 (G1) and 6 times (G2). Afterward, animals in G1 were punctured at 5-week intervals 9 times after FSH superstimulation to obtain in vivo matured COC at the metaphase II stage. Data were analysed using a mixed model (SAS). In the twice-weekly OPU for G1 and G2 combined, significantly (P < 0.05) more COC per animal and OPU session were obtained from the old cows (9.9 ± 1.0) compared with heifers and young cows (6.0 ± 0.8 and 7.0 ± 1.0, respectively). When G1 and G2 were regarded separately, lower numbers of COC (P < 0.01) were obtained in G1 than in G2 (2.7 ± 0.8, 4.4 ± 0.8, 7.0 ± 0.8 and 9.2 ± 1.5, 9.4 ± 2.3, 12.9 ± 2.3 for heifers, young cows, and old cows of G1 and G2, respectively). Cleavage rates (CR) on day 3 after IVF (day 0) were not affected by donor age and were not different between groups. Cultivation of COC from young cows in G1 led to higher blastocyst rates (BR) on day 7 (P < 0.05) compared with old cows and heifers. No differences in BR were observed between animals of G2. Significantly more COC (P < 0.01) were obtained in all age groups from FSH superstimulated donors (10.6 ± 0.8, 9.0 ± 0.9, and 11.7 ± 0.9 for heifers, young cows, and old cows, respectively). Cleavage rates and BR were significantly higher (P < 0.05) in all age groups after FSH superstimulation compared with those of nonstimulated donors. However, there were no differences in CR and BR between age groups (CR: 82.8 ± 7.0, 89.9 ± 7.0, 77.1 ± 6.2%; BR: 34.4 ± 7.2, 44.6 ± 7.2, 36.7 ± 7.2%). We conclude that although the numbers of COC obtained per animal and session were significantly different between G1 and G2, in vitro results were highly repeatable after OPU without hormonal prestimulation. Higher CR and BR were obtained after IVF of in vivo matured COC obtained from FSH superstimulated donors, regardless of animal age. This work was supported by the Deutsche Forschungsgemeinschaft (FOR 1041).

scholarly journals ID3019 Female germline stem Cells: A source for application in reproductive and regenerative medicine

2017 ◽  
Vol 4 (S) ◽  
pp. 31
Author(s):  
Thuy Hong Bui
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Ovarian Function ◽  
Primordial Germ Cells ◽  
Postnatal Life ◽  
Proliferative Potential ◽  
Germline Stem Cells ◽  
Mammalian Female ◽  
Female Germline

Studies suggest a renewable source of eggs and stir more controversy, especially about the origin of female germline stem cells (FGSCs). It should be elucidated whether or not neo-oogenesis continues in the ovaries of mammalian female during postnatal life. Therefore, the establishment of FGSCs is very important for many applications. Here, using adult pig ovary, we isolate, identify, characterize FGSCs to elucidate their origin, then examined the proliferation, growth and differentiation of them. These cells were heterogeneous, depending on both of c-kit expression and cell size, and also express stem cell and germ cell markers. Importantly, we show clearly that the cells with the characteristics of early primordial germ cells are present in the adult pig ovary. Once FGSCs were established, they could be expanded in vitro for months without loss of the identifying markers and proliferative potential. Under appropriate conditions, the FGSCs differentiated into primordial oocyte-like cells and grow close to full-sized oocytes. These may assist in therapeutic strategies in human with their potential to make new oocytes and support ovarian function and fertility. Our results support the theory that the ovary contains a small number of undifferentiated cells with stem cell characteristics. These might remain in the postnatal and adult ovary and under certain conditions could resume mitosis, enter meiosis and give rise to oocytes. Given the existence of these FGSCs in mammalian ovaries and the depletion in ovarian reserve during female reproductive aging, one can hypothesize that such “neo-oogenesis” was present in ancestral forms, is still present in insects, some fish and mollusks, but has been lost in land vertebrates through evolution. FGSCs cannot proliferate in the ovary normally because of inhibitory factors, but under appropriate conditions, they can undergo proliferation and differentiation, and provide a potential mechanism for the self-renewal of germline stem cells.

scholarly journals Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Hong Chen ◽  
Kai Xia ◽  
Weijun Huang ◽  
Huijian Li ◽  
Chao Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ovarian Function ◽  
Autologous Transplantation ◽  
Fertilization Rate ◽  
Vital Role ◽  
Ovarian Activity ◽  
New Strategy ◽  
First Time ◽  
Human Primate

AbstractPremature ovarian insufficiency (POI) is defined as the loss of ovarian activity under the age of 40. Theca cells (TCs) play a vital role during folliculogenesis and TCs dysfunction participate in the pathogenesis of POI. Therefore, transplantation of thecal stem cells (TSCs), which are capable of self-renewal and differentiation into mature TCs, may provide a new strategy for treating POI. To investigate the feasibility, safety, and efficacy of TSCs transplantation in clinically relevant non-human primate (NHP) models, we isolate TSCs from cynomolgus monkeys, and these cells are confirmed to expand continuously and show potential to differentiate into mature TCs. In addition, engraftment of autologous TSCs into POI monkeys significantly improves hormone levels, rescues the follicle development, promotes the quality of oocytes and boosts oocyte maturation/fertilization rate. Taken together, these results for the first time suggest that autologous TSCs can ameliorate POI symptoms in primate models and shed new light on developing stem cell therapy for POI.

scholarly journals The Hippo Signaling Pathway Regulates Ovarian Function via the Proliferation of Ovarian Germline Stem Cells

2017 ◽  
Vol 41 (3) ◽  
pp. 1051-1062 ◽  
Author(s):  
Haifeng Ye ◽  
Xiaoyan Li ◽  
Tuochen Zheng ◽  
Chuan Hu ◽  
Zezheng Pan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Birth Rate ◽  
Ovarian Function ◽  
Reproductive Age ◽  
Hippo Signaling ◽  
Germline Stem Cells ◽  
Hippo Signaling Pathway ◽  
Proliferation And Differentiation

Objective: To improve the separation, identification and cultivation of ovarian germline stem cells (OGSCs), to clarify the relationship between the Hippo signaling pathway effector YAP1 and the proliferation and differentiation of OGSCs in vitro and to identify the major contribution of Hippo signaling to ovarian function. Methods: Two-step enzymatic separation processes and magnetic separation were used to isolate and identify OGSCs by determining the expression of Mvh, Oct4, Nanog, Fragilis and Stella markers. Then, YAP1, as the main effector molecule in the Hippo signaling pathway, was chosen as the target gene of the study. Lentivirus containing overexpressed YAP1 or a YAP1-targeted shRNA was transduced into OGSCs. The effects of modulating the Hippo signaling pathway on the proliferation, differentiation, reproduction and endocrine function of ovaries were observed by microinjecting the lentiviral vectors with overexpressed YAP1 or YAP1 shRNA into infertile mouse models or natural mice of reproductive age. Results: (1) The specific expression of Mvh, Oct4, Nanog, Fragilis and Stella markers was observed in isolated stem cells. Thus, the isolated cells were preliminarily identified as OGSCs. (2) The co-expression of LATS2, MST1, YAP1 and MVH was observed in isolated OGSCs. Mvh and Oct4 expression levels were significantly increased in OGSCs overexpressing YAP1 compared to GFP controls. Consistently, Mvh and Oct4 levels were significantly decreased in cells expressing YAP1-targeted shRNA. (3) After 14-75 days of YAP1 overexpression in infertile mouse models, we detected follicle regeneration in ovaries, the activation of primordial follicles and increased birth rate, accompanied by increasing levels of E2 and FSH. (4) However, we detected decreasing follicles in ovaries, lower birth rate, and decreasing E2 and FSH in serum from healthy mice of reproductive age following YAP1 shRNA expression. Conclusion: Methods for the isolation, identification and culture of OGSCs were successfully established. Further results indicate that isolated OGSCs can specifically recognize Hippo signaling molecules and that manipulation of YAP1 expression can be used to regulate the proliferation and differentiation of OGSCs, as well as ovarian function in mice. This study suggests that the Hippo signaling pathway may represent a new molecular target for the regulation of mouse ovarian functional remodeling.

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