Male germline stem cells in non-human primates

Abstract. Over the past few decades, several studies have attempted to decipher the biology of mammalian germline stem cells (GSCs). These studies provide evidence that regulatory mechanisms for germ cell specification and migration are evolutionarily conserved across species. The characteristics and functions of primate GSCs are highly distinct from rodent species; therefore the findings from rodent models cannot be extrapolated to primates. Due to limited availability of human embryonic and testicular samples for research purposes, two non-human primate models (marmoset and macaque monkeys) are extensively employed to understand human germline development and differentiation. This review provides a broader introduction to the in vivo and in vitro germline stem cell terminology from primordial to differentiating germ cells. Primordial germ cells (PGCs) are the most immature germ cells colonizing the gonad prior to sex differentiation into testes or ovaries. PGC specification and migratory patterns among different primate species are compared in the review. It also reports the distinctions and similarities in expression patterns of pluripotency markers (OCT4A, NANOG, SALL4 and LIN28) during embryonic developmental stages, among marmosets, macaques and humans. This review presents a comparative summary with immunohistochemical and molecular evidence of germ cell marker expression patterns during postnatal developmental stages, among humans and non-human primates. Furthermore, it reports findings from the recent literature investigating the plasticity behavior of germ cells and stem cells in other organs of humans and monkeys. The use of non-human primate models would enable bridging the knowledge gap in primate GSC research and understanding the mechanisms involved in germline development. Reported similarities in regulatory mechanisms and germ cell expression profile in primates demonstrate the preclinical significance of monkey models for development of human fertility preservation strategies.

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Expression Profiling of Mammalian Male Meiosis and Gametogenesis Identifies Novel Candidate Genes for Roles in the Regulation of Fertility

Molecular Biology of the Cell ◽

10.1091/mbc.e03-10-0762 ◽

2004 ◽

Vol 15 (3) ◽

pp. 1031-1043 ◽

Cited By ~ 97

Author(s):

Ulrich Schlecht ◽

Philippe Demougin ◽

Reinhold Koch ◽

Leandro Hermida ◽

Christa Wiederkehr ◽

...

Keyword(s):

Germ Cell ◽

Germ Cells ◽

Expression Profiling ◽

Large Scale ◽

Developmental Stages ◽

Expression Patterns ◽

Control Cell ◽

Cell Types ◽

Male Meiosis ◽

Cell Expression

We report a comprehensive large-scale expression profiling analysis of mammalian male germ cells undergoing mitotic growth, meiosis, and gametogenesis by using high-density oligonucleotide microarrays and highly enriched cell populations. Among 11,955 rat loci investigated, 1268 were identified as differentially transcribed in germ cells at subsequent developmental stages compared with total testis, somatic Sertoli cells as well as brain and skeletal muscle controls. The loci were organized into four expression clusters that correspond to somatic, mitotic, meiotic, and postmeiotic cell types. This work provides information about expression patterns of ∼200 genes known to be important during male germ cell development. Approximately 40 of those are included in a group of 121 transcripts for which we report germ cell expression and lack of transcription in three somatic control cell types. Moreover, we demonstrate the testicular expression and transcriptional induction in mitotic, meiotic, and/or postmeiotic germ cells of 293 as yet uncharacterized transcripts, some of which are likely to encode factors involved in spermatogenesis and fertility. This group also contains potential germ cell-specific targets for innovative contraceptives. A graphical display of the data is conveniently accessible through the GermOnline database at http://www.germonline.org .

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The Controversy, Challenges, and Potential Benefits of Putative Female Germline Stem Cells Research in Mammals

Stem Cells International ◽

10.1155/2016/1728278 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Zezheng Pan ◽

Mengli Sun ◽

Xia Liang ◽

Jia Li ◽

Fangyue Zhou ◽

...

Keyword(s):

Stem Cells ◽

Germ Cell ◽

Germ Cells ◽

Mammalian Species ◽

Research Progress ◽

Germline Stem Cells ◽

Conventional View ◽

Proliferation And Differentiation ◽

Potential Benefits ◽

Female Germline

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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Nanos and Pumilio have critical roles in the development and function of Drosophila germline stem cells

Development ◽

10.1242/dev.125.4.679 ◽

1998 ◽

Vol 125 (4) ◽

pp. 679-690 ◽

Cited By ~ 47

Author(s):

A. Forbes ◽

R. Lehmann

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Germ Cells ◽

Rna Binding ◽

Drosophila Embryo ◽

Germline Stem Cell ◽

Germline Stem Cells ◽

Embryonic Patterning ◽

Germline Development ◽

Egg Chambers

The zinc-finger protein Nanos and the RNA-binding protein Pumilio act together to repress the translation of maternal hunchback RNA in the posterior of the Drosophila embryo, thereby allowing abdomen formation. nanos RNA is localized to the posterior pole during oogenesis and the posteriorly synthesized Nanos protein is sequestered into the germ cells as they form in the embryo. This maternally provided Nanos protein is present in germ cells throughout embryogenesis. Here we show that maternally deposited Nanos protein is essential for germ cell migration. Lack of zygotic activity of nanos and pumilio has a dramatic effect on germline development of homozygous females. Given the coordinate function of nanos and pumilio in embryonic patterning, we analyzed the role of these genes in oogenesis. We find that both genes act in the germline. Although the nanos and pumilio ovarian phenotypes have similarities and both genes ultimately affect germline stem cell development, the focus of these phenotypes appears to be different. While pumilio mutant ovaries fail to maintain stem cells and all germline cells differentiate into egg chambers, the focus of nanos function seems to lie in the differentiation of the stem cell progeny, the cystoblast. Consistent with the model that nanos and pumilio have different phenotypic foci during oogenesis, we detect high levels of Pumilio protein in the germline stem cells and high levels of Nanos in the dividing cystoblasts. We therefore suggest that, in contrast to embryonic patterning, Nanos and Pumilio may interact with different partners in the germline.

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Mouse Germ Cell Development in-vivo and in-vitro

Biomarker Insights ◽

10.1177/117727190700200024 ◽

2007 ◽

Vol 2 ◽

pp. 117727190700200 ◽

Cited By ~ 15

Author(s):

Deshira Saiti ◽

Orly Lacham-Kaplan

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Germ Cell ◽

Germ Cells ◽

Expression Patterns ◽

Embryonic Stem ◽

Cell Lineage ◽

Initial Population

In mammalian development, primordial germ cells (PGCs) represent the initial population of cells that are committed to the germ cell lineage. PGCs segregate early in development, triggered by signals from the extra-embryonic ectoderm. They are distinguished from surrounding cells by their unique gene expression patterns. Some of the more common genes used to identify them are Blimp1, Oct3/4, Fragilis, Stella, c-Kit, Mvh, Dazl and Gcna1. These genes are involved in regulating their migration and differentiation, and in maintaining the pluripotency of these cells. Recent research has demonstrated the possibility of obtaining PGCs, and subsequently, mature germ cells from a starting population of embryonic stem cells (ESCs) in culture. This phenomenon has been investigated using a variety of methods, and ESC lines of both mouse and human origin. Embryonic stem cells can differentiate into germ cells of both the male and female phenotype and in one case has resulted in the birth of live pups from the fertilization of oocytes with ESC derived sperm. This finding leads to the prospect of using ESC derived germ cells as a treatment for sterility. This review outlines the evolvement of germ cells from ESCs in vitro in relation to in vivo events.

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Early Drosophila Oogenesis: A Tale of Centriolar Asymmetry

Cells ◽

10.3390/cells10081997 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1997

Author(s):

Maria Giovanna Riparbelli ◽

Veronica Persico ◽

Giuliano Callaini

Keyword(s):

Stem Cells ◽

Dna Replication ◽

Germ Cell ◽

Developmental Stages ◽

Germline Stem Cells ◽

Drosophila Oogenesis ◽

Early Stages ◽

Duplication Events ◽

Morphological Processes ◽

Oocyte Selection

Among the morphological processes that characterize the early stages of Drosophila oogenesis, the dynamic of the centrioles deserves particular attention. We re-examined the architecture and the distribution of the centrioles within the germarium and early stages of the vitellarium. We found that most of the germ cell centrioles diverge from the canonical model and display notable variations in size. Moreover, duplication events were frequently observed within the germarium in the absence of DNA replication. Finally, we report the presence of an unusually long centriole that is first detected in the cystoblast and is always associated with the developing oocyte. This centriole is directly inherited after the asymmetric division of the germline stem cells and persists during the process of oocyte selection, thus already representing a marker for oocyte identification at the beginning of its formation and during the ensuing developmental stages.

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A role for the Drosophila bag-of-marbles protein in the differentiation of cystoblasts from germline stem cells

Development ◽

10.1242/dev.121.9.2937 ◽

1995 ◽

Vol 121 (9) ◽

pp. 2937-2947 ◽

Cited By ~ 52

Author(s):

D. McKearin ◽

B. Ohlstein

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Cell Differentiation ◽

Germ Cell ◽

Germ Cells ◽

Germline Stem Cell ◽

Cytoplasmic Protein ◽

Germline Stem Cells ◽

Bag Of Marbles

Cell differentiation commonly dictates a change in the cell cycle of mitotic daughters. Previous investigations have suggested that the Drosophila bag of marbles (bam) gene is required for the differentiation of germline stem cell daughters (cystoblasts) from the mother stem cells, perhaps by altering the cell cycle. In this paper, we report the preparation of antibodies to the Bam protein and the use of those reagents to investigate how Bam is required for germ cell development. We find that Bam exists as both a fusome component and as cytoplasmic protein and that cytoplasmic and fusome Bam might have separable activities. We also show that bam mutant germ cells are blocked in differentiation and are trapped as mitotically active cells like stem cells. A model for how Bam might regulate cystocyte differentiation is presented.

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The reversible developmental unipotency of germ cells in chicken

Reproduction ◽

10.1530/rep-09-0265 ◽

2010 ◽

Vol 139 (1) ◽

pp. 113-119 ◽

Cited By ~ 16

Author(s):

Jin Gyoung Jung ◽

Young Mok Lee ◽

Jin Nam Kim ◽

Tae Min Kim ◽

Ji Hye Shin ◽

...

Keyword(s):

Stem Cells ◽

Germ Cell ◽

Germ Cells ◽

Developmental Stages ◽

Production Systems ◽

Primordial Germ Cells ◽

Transmission Efficiency ◽

Germline Transmission ◽

Adult Testis

We recently developed bimodal germline chimera production approaches by transfer of primordial germ cells (PGCs) or embryonic germ cells (EGCs) into embryos and by transplantation of spermatogonial stem cells (SSCs) or germline stem cells (GSCs) into adult testes. This study was undertaken to investigate the reversible developmental unipotency of chicken germ cells using our established germline chimera production systems. First, we transferred freshly isolated SSCs from adult testis or in vitro cultured GSCs into stage X and stage 14–16 embryos, and we found that these transferred SSCs/GSCs could migrate to the recipient embryonic gonads. Of the 527 embryos that received SSCs or GSCs, 135 yielded hatchlings. Of 17 sexually mature males (35.3%), six were confirmed as germline chimeras through testcross analysis resulting in an average germline transmission efficiency of 1.3%. Second, PGCs/EGCs, germ cells isolated from embryonic gonads were transplanted into adult testes. The EGC transplantation induced germline transmission, whereas the PGC transplantation did not. The germline transmission efficiency was 12.5 fold higher (16.3 vs 1.3%) in EGC transplantation into testis (EGCs to adult testis) than that in SSC/GSC transfer into embryos (testicular germ cells to embryo stage). In conclusion, chicken germ cells from different developmental stages can (de)differentiate into gametes even after the germ cell developmental clock is set back or ahead. Use of germ cell reversible unipotency might improve the efficiency of germ cell-mediated germline transmission.

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Krüppel-like factor 4 is required for development and regeneration of germline and yolk cells from somatic stem cells in planarians

10.1101/2021.11.08.467675 ◽

2021 ◽

Author(s):

Melanie Issigonis ◽

Akshada Redkar ◽

Tania Rozario ◽

Umair Khan ◽

Rosa Mejia-Sanchez ◽

...

Keyword(s):

Stem Cells ◽

Germ Cell ◽

Germ Cells ◽

System Development ◽

Primordial Germ Cells ◽

Reproductive Organs ◽

Germline Stem Cells ◽

Yolk Cell ◽

Evolutionary Innovation ◽

Parasitic Flatworm

Sexually reproducing animals segregate their germline from their soma. In addition to gamete-producing gonads, planarian and parasitic flatworm reproduction relies on yolk-cell-generating accessory reproductive organs (vitellaria) supporting development of yolkless oocytes. Despite the importance of vitellaria for flatworm reproduction (and parasite transmission), little is known about this unique evolutionary innovation. Here we examine reproductive system development in the planarian Schmidtea mediterranea, in which pluripotent stem cells generate both somatic and germ cell lineages. We show that a homolog of the pluripotency factor Klf4 is expressed in primordial germ cells, presumptive germline stem cells, and yolk-cell progenitors. klf4 knockdown animals fail to specify or maintain germ cells; surprisingly, they also fail to maintain yolk cells. We find that yolk cells display germ-cell-like attributes and that vitellaria are structurally analogous to gonads. In addition to identifying a new proliferative cell population in planarians (yolk cell progenitors) and defining its niche, our work provides evidence supporting the hypothesis that flatworm germ cells and yolk cells share a common evolutionary origin.

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Defining the expression of piRNA and transposable elements in Drosophila ovarian germline stem cells and somatic support cells

Life Science Alliance ◽

10.26508/lsa.201800211 ◽

2019 ◽

Vol 2 (5) ◽

pp. e201800211 ◽

Cited By ~ 3

Author(s):

Benjamin Story ◽

Xing Ma ◽

Kazue Ishihara ◽

Hua Li ◽

Kathryn Hall ◽

...

Keyword(s):

Stem Cells ◽

Transposable Elements ◽

Germ Cell ◽

Germ Cells ◽

Genome Stability ◽

Cell Function ◽

Germline Stem Cells ◽

Sequencing Data ◽

Rich Information ◽

The Rich

Piwi-interacting RNAs (piRNAs) are important for repressing transposable elements (TEs) and modulating gene expression in germ cells, thereby maintaining genome stability and germ cell function. Although they are also important for maintaining germline stem cells (GSCs) in the Drosophila ovary by repressing TEs and preventing DNA damage, piRNA expression has not been investigated in GSCs or their early progeny. Here, we show that the canonical piRNA clusters are more active in GSCs and their early progeny than late germ cells and also identify more than 3,000 new piRNA clusters from deep sequencing data. The increase in piRNAs in GSCs and early progeny can be attributed to both canonical and newly identified piRNA clusters. As expected, piRNA clusters in GSCs, but not those in somatic support cells (SCs), exhibit ping-pong signatures. Surprisingly, GSCs and early progeny express more TE transcripts than late germ cells, suggesting that the increase in piRNA levels may be related to the higher levels of TE transcripts in GSCs and early progeny. GSCs also have higher piRNA levels and lower TE levels than SCs. Furthermore, the 3′ UTRs of 171 mRNA transcripts may produce sense, antisense, or dual-stranded piRNAs. Finally, we show that alternative promoter usage and splicing are frequently used to modulate gene function in GSCs and SCs. Overall, this study has provided important insight into piRNA production and TE repression in GSCs and SCs. The rich information provided by this study will be a beneficial resource to the fields of piRNA biology and germ cell development.

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Germ cells: ENCODE’s forgotten cell type

Biology of Reproduction ◽

10.1093/biolre/ioab135 ◽

2021 ◽

Author(s):

John R McCarrey ◽

Keren Cheng

Keyword(s):

Stem Cells ◽

Germ Cell ◽

Somatic Cell ◽

Germ Cells ◽

Developmental Stages ◽

Cell Types ◽

Recent Effort ◽

Cell Type ◽

Male And Female ◽

Genome Wide

Abstract More than a decade ago, the ENCODE and NIH Epigenomics Roadmap consortia organized large multi-laboratory efforts to profile the epigenomes of >110 different mammalian somatic cell types. This generated valuable publicly accessible datasets that are being mined to reveal genome-wide patterns of a variety of different epigenetic parameters. This consortia approach facilitated the powerful and comprehensive multiparametric integrative analysis of the epigenomes in each cell type. However, no germ cell types were included among the cell types characterized by either of these consortia. Thus, comprehensive epigenetic profiling data is not generally available for the most evolutionarily important cells, male and female germ cells. We discuss the need for reproductive biologists to generate similar multiparametric epigenomic profiling datasets for both male and female germ cells at different developmental stages, and summarize our recent effort to derive such data for mammalian spermatogonial stem cells and progenitor spermatogonia.

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