scholarly journals Ovarian Stem Cells–-the Pros and Cons

2013 ◽  
Vol 7 ◽  
pp. CMRH.S11086 ◽  
Author(s):  
Ayelet Evron ◽  
Zeev Blumenfeld
Keyword(s):  
Stem Cells ◽  
Cell Biology ◽  
De Novo ◽  
Germ Line ◽  
Mammalian Species ◽  
Primordial Follicle ◽  
Reproductive Age ◽  
Primordial Follicles ◽  
Pros And Cons ◽  
Reproductive Science

The potential for postnatal de novo oogenesis in mammals and in humans has become very controversial in the fields of reproductive science and biology. Historically, it has been thought that females of most mammalian species lose the ability to produce oocytes at birth. A contemporary understanding of stem cell biology together with novel experimental methods has challenged the model of a prenatal fixed ovarian primordial follicle pool that declines with age. Researchers have suggested replenishment of post-natal oocytes by germ-line stem cells (GSCs). According to this theory, GSCs produce oocytes and primordial follicles throughout the lifetime of the adult female. This review describes recent approaches supporting the revolutionary idea of de novo oogenesis in mammals and humans of reproductive-age and provides counter arguments from opponents of this novel and innovative concept.

scholarly journals The primordial follicle reserve is not renewed after chemical or γ-irradiation mediated depletion

Reproduction ◽  
2012 ◽  
Vol 143 (4) ◽  
pp. 469-476 ◽  
Author(s):  
J B Kerr ◽  
L Brogan ◽  
M Myers ◽  
K J Hutt ◽  
T Mladenovska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germ Line ◽  
Trichostatin A ◽  
Primordial Follicle ◽  
Whole Body ◽  
Postnatal Life ◽  
Γ Irradiation ◽  
Primordial Follicles ◽  
Adult Mice ◽  
Complete Ablation

Reports indicate that germ-line stem cells present in adult mice can rapidly generate new oocytes and contribute to the primordial follicle reserve following conditions of ovotoxic stress. We further investigated the hypothesis that adult mice have the capacity to generate new oocytes by monitoring primordial follicle numbers throughout postnatal life and following depletion of the primordial follicle reserve by exposure to doxorubicin (DXR), trichostatin A (TSA), or whole-body γ-irradiation. We show that primordial follicle number remains stable in adult C57BL/6 mice between the ages of 25 and 100 days. However, within 2 days of treatment with DXR or TSA, primordial follicle numbers had declined to 65 and 51% respectively (P<0.05–0.01 when compared to untreated controls), with no restoration of follicle numbers evident after 7 days for either treatment. Furthermore, ovaries from mice subjected to sterilizing doses of γ-irradiation (0.45 or 4.5 Gy) revealed complete ablation of all primordial follicles 5 days after treatment, with no indication of follicular renewal. We conclude that neo-folliculogenesis does not occur following chemical or γ-irradiation mediated depletion of the primordial follicle reserve.

scholarly journals Epigenetic marking and repression of porcine endogenous retroviruses

2013 ◽  
Vol 94 (5) ◽  
pp. 960-970 ◽  
Author(s):  
Gernot Wolf ◽  
Anders Lade Nielsen ◽  
Jacob Giehm Mikkelsen ◽  
Finn Skou Pedersen
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Germ Line ◽  
Mammalian Species ◽  
Histone Deacetylation ◽  
Endogenous Retroviruses ◽  
Primer Binding Site ◽  
Retroviral Transduction ◽  
Embryonic Germ Cells ◽  
Epigenetic Repression

Endogenous retroviruses (ERVs) are remnants of retroviral germ line infections and have been identified in all mammals investigated so far. Although the majority of ERVs are degenerated, some mammalian species, such as mice and pigs, carry replication-competent ERVs capable of forming infectious viral particles. In mice, ERVs are silenced by DNA methylation and histone modifications and some exogenous retroviruses were shown to be transcriptionally repressed after integration by a primer-binding site (PBS) targeting mechanism. However, epigenetic repression of porcine ERVs (PERVs) has remained largely unexplored so far. In this study, we screened the pig genome for PERVs using LTRharvest, a tool for de novo detection of ERVs, and investigated various aspects of epigenetic repression of three unrelated PERV families. We found that these PERV families are differentially up- or downregulated upon chemical inhibition of DNA methylation and histone deacetylation in cultured porcine cells. Furthermore, chromatin immunoprecipitation analysis revealed repressive histone methylation marks at PERV loci in primary porcine embryonic germ cells and immortalized embryonic kidney cells. PERV elements belonging to the PERV-γ1 family, which is the only known PERV family that has remained active up to the present, were marked by significantly higher levels of histone methylations than PERV-γ2 and PERV-β3 proviruses. Finally, we tested three PERV-associated PBS sequences for repression activity in murine and porcine cells using retroviral transduction experiments and showed that none of these PBS sequences induced immediate transcriptional silencing in the tested primary porcine cells.

scholarly journals Specificity of the requirement for Foxo3 in primordial follicle activation

Reproduction ◽  
2007 ◽  
Vol 133 (5) ◽  
pp. 855-863 ◽  
Author(s):  
George B John ◽  
Lane J Shirley ◽  
Teresa D Gallardo ◽  
Diego H Castrillon
Keyword(s):  
Germ Line ◽  
Primordial Follicle ◽  
Forkhead Transcription Factor ◽  
Primordial Follicles ◽  
Mouse Mutants ◽  
Physiological Processes ◽  
Primordial Follicle Activation ◽  
Mammalian Female ◽  
Structure Assembly ◽  
Follicle Activation

Primordial follicles are long-lived structures assembled early in life. The mechanisms that control the balance between the conservation and the activation of primordial follicles are critically important for fertility and dictate the onset of menopause. The forkhead transcription factor Foxo3 serves an essential role in these processes by suppressing the growth of primordial follicles, thereby preserving them until later in life. While other factors regulating primordial follicle growth have been described, most serve multiple functions at several stages of female germ cell or follicle development, and corresponding mouse mutants exhibit pleiotropic phenotypes with disruption of multiple stages of follicle assembly, development, or survival. To investigate the possibility that Foxo3 also functions in other aspects of ovarian development beyond its known role in primordial follicle activation (PFA), we performed detailed analyses of mouse ovaries including electron microscopy to study primordial follicle structure, assembly, and early growth. These analyses revealed that the timing of primordial follicle assembly, early oocyte survival, and the expression of early germ line markers were unaffected in early Foxo3 ovaries. Taken together, these studies demonstrate that the phenotype associated with Foxo3 deficiency is remarkably specific for PFA and further support the placement of Foxo3 in a unique phenotypic class among mammalian female sterile mutants. Lastly, we discuss the implications of the specificity of this mutant phenotype with regard to the hypothesis that oocyte regeneration may occur in adults and serves as a means to replenish oocytes lost via natural physiological processes.

Attempts towards derivation and establishment of bovine embryonic stem cell-like cultures

2005 ◽  
Vol 17 (2) ◽  
pp. 113 ◽  
Author(s):  
Poul Maddox-Hyttel ◽  
Jakob O. Gjørret
Keyword(s):  
Stem Cells ◽  
Adult Stem Cells ◽  
Germ Line ◽  
Current Knowledge ◽  
Mammalian Species ◽  
Embryonic Stem ◽  
Transgenic Animals ◽  
Great Expectations ◽  
Safety Issues ◽  
Germ Line Transmission

Current knowledge on the biology of mammalian embryonic stem cells (ESC) is stunningly sparse in light of their potential value in studies of development, functional genomics, generation of transgenic animals and human medicine. Despite many efforts to derive ESC from other mammalian species, ESC that retain their capacity for germ line transmission have only been verified in the mouse. However, the criterion of germ line transmission may not need to be fulfilled for exploitation of other abilities of these cells. Promising results with human ESC-like cells and adult stem cells have nourished great expectations for their potential use in regenerative medicine. However, such an application is far from reality and substantial research is required to elucidate aspects of the basic biology of pluripotent cells, as well as safety issues associated with the use of such cells in therapy. In this context, methods for the derivation, propagation and differentiation of ESC-like cultures from domestic animals would be highly desirable as biologically relevant models. Here, we review previously published efforts to establish bovine ESC-like cells and describe a procedure used in attempts to derive similar cells from bovine Day 12 embryos.

The Role of Nucleophosmin In Hematopoietic Stem Cells and the Pathogenesis of Myelodysplastic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 95-95 ◽  
Author(s):  
Keisuke Ito ◽  
Paolo Sportoletti ◽  
John G Clohessy ◽  
Grisendi Silvia ◽  
Pier Paolo Pandolfi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Cell Biology ◽  
De Novo ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

Abstract Abstract 95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Follicular assembly: mechanisms of action

Reproduction ◽  
2012 ◽  
Vol 143 (2) ◽  
pp. 139-149 ◽  
Author(s):  
Melissa E Pepling
Keyword(s):  
Cell Death ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Mechanisms Of Action ◽  
Initial Number ◽  
Primordial Follicles ◽  
Meiotic Progression ◽  
Germ Cell Cysts ◽  
Reproductive Cancers

The differentiation of primordial germ cells (PGCs) into functional oocytes is important for the continuation of species. In mammals, PGCs begin to differentiate into oocytes during embryonic development. Oocytes develop in clusters called germ line cysts. During fetal or neonatal development, germ cell cysts break apart into single oocytes that become surrounded by pregranulosa cells to form primordial follicles. During the process of cyst breakdown, a subset of cells in each cyst undergoes cell death with only one-third of the initial number of oocytes surviving to form primordial follicles. The mechanisms that control cyst breakdown, oocyte survival, and follicle assembly are currently under investigation. This review describes the mechanisms that have been implicated in the control of primordial follicle formation, which include programmed cell death regulation, growth factor and other signaling pathways, regulation by transcription factors and hormones, meiotic progression, and changes in cell adhesion. Elucidation of mechanisms leading to formation of the primordial follicle pool will help research efforts in ovarian biology and improve treatments of female infertility, premature ovarian failure, and reproductive cancers.

Developing a Model of Human Pluripotent to Hematopoietic Stem Cell Development in Mistrg Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4755-4755
Author(s):  
John Astle ◽  
Yangfei Xiang ◽  
Anthony Rongvaux ◽  
Carla Weibel ◽  
Henchey Elizabeth ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice

Abstract De novo generation of HSCs has been described as a "holy grail" of stem cell biology, however the factors required for converting human pluripotent stem cells (PSCs) to true hematopoietic stem cells (HSCs) capable of robust long-term engraftment have yet to be fully characterized. Two groups have shown that injection of PSCs into immunodeficient mice leads to teratomas containing niches producing hematopoietic progenitors capable of long-term engraftment. Once these hematopoietic progenitors and their microenvironments are better characterized, this system could be used as a model to help direct in vitro differentiation of PSCs to HSCs. Toward this end, we have injected human PSCs into immunodeficient mice expressing human rather than mouse M-CSF, IL-3, GM-CSF, and thrombopoietin, as well as both human and mouse versions of the "don't eat me signal" Sirpa (collectively termed MISTRG mice). These cytokines are known to support different aspects of hematopoiesis, and thrombopoietin in particular has been shown to support HSC maintenance, suggesting these mice may provide a better environment for human PSC-derived HSCs than the more traditional mice used for human HSC engraftment. The majority of teratomas developed so far in MISTRG contain human hematopoietic cells, and the CD34+ population isolated from over half of the teratomas contained hematopoietic colony forming cells by colony forming assay. These findings further corroborate this approach as a viable method for studying human PSC to HSC differentiation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply

Reproduction ◽  
2006 ◽  
Vol 132 (1) ◽  
pp. 95-109 ◽  
Author(s):  
J B Kerr ◽  
R Duckett ◽  
M Myers ◽  
K L Britt ◽  
T Mladenovska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Primordial Follicle ◽  
Meiotic Maturation ◽  
Nuclear Antigen ◽  
Surface Epithelium ◽  
Postnatal Life ◽  
Germline Stem Cells ◽  
Primordial Follicles ◽  
Oocyte Meiosis ◽  
Mitotic Figures

Proliferation and partial meiotic maturation of germ cells in fetal ovaries is believed to establish a finite, non-renewable pool of primordial follicles at birth. The supply of primordial follicles in postnatal life should be depleted during folliculogenesis, either undergoing atresia or surviving to ovulation. Recent studies of mouse ovaries propose that intra- and extraovarian germline stem cells replenish oocytes and form new primordial follicles. We quantified all healthy follicles in C57BL/6 mouse ovaries from day 1 to 200 using unbiased stereological methods, immunolabelling of oocyte meiosis (germ cell nuclear antigen (GCNA)) and ovarian cell proliferation (proliferating cell nuclear antigen (PCNA)) and electronmicroscopy. Day 1 ovaries contained 7924±1564 (s.e.m.) oocytes or primordial follicles, declining on day 7 to 1987±203, with 200–800 oocytes ejected from individual ovaries on that day and day 12. Discarded oocytes and those subjacent to the surface epithelium were GCNA-positive indicating their incomplete meiotic maturation. From day 7 to 100 mean numbers of primordial follicles per ovary were not significantly depleted but declined at 200 days to 254±71. Mean numbers of all healthy follicles per ovary were not significantly different from day 7 to 100 (range 2332±349–3007±322). Primordial follicle oocytes were PCNA-negative. Occasional unidentified cells were PCNA-positive with mitotic figures observed in the cortex of day 1 and 12 ovaries. Although we found no evidence for ovarian germline stem cells, our data support the hypothesis of postnatal follicle renewal in postnatal and adult ovaries of C57BL/6 mice.

scholarly journals Combating ovarian aging depends on the use of existing ovarian follicles, not on putative oogonial stem cells

Reproduction ◽  
2013 ◽  
Vol 146 (6) ◽  
pp. R229-R233 ◽  
Author(s):  
Hua Zhang ◽  
Deepak Adhikari ◽  
Wenjing Zheng ◽  
Kui Liu
Keyword(s):  
Stem Cells ◽  
Egg Quality ◽  
Mammalian Species ◽  
Adult Life ◽  
Ovarian Follicles ◽  
Primordial Follicles ◽  
The Past ◽  
Ovarian Aging ◽  
Promising Source ◽  
Fixed Population

Ovarian aging is characterized by both a reduction in egg quality and a drastic reduction in the number of ovarian follicles. It has been generally accepted for 60 years that a fixed population of primordial follicles is established in the ovaries during early life, and in most mammalian species, oocytes cannot renew themselves in postnatal or adult life. This dogma, however, has been challenged over the past decade. In this review, we summarize the recent studies on primordial follicles and putative oogonial stem cells and discuss what resources in the ovary might be more reliable and promising source tools for combating ovarian aging.

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