germline stem cell

Karen Makar, Kotaro Sasaki
BACKGROUND: The germ cell lineage is the fundamental component of the metazoan life cycle as it ensures the perpetuation and diversification of genetic information across generations. Recent advances in the understanding of germ cell development in mice have culminated in the ability to reconstitute gametogenesis in vitro, thereby enabling the biochemical and molecular analyses of germ cell specification and subsequent development in mice. Similar advances in reconstituting human germ cells in vitro would provide critical insight into the etiology of various reproductive conditions and disorders, including infertility...
November 9, 2019: Andrology
Arina Riabinska, Daria Lehrmann, Ron Daniel Jachimowicz, Gero Knittel, Christian Fritz, Anna Schmitt, Aenne Geyer, Carola Heneweer, Maike Wittersheim, Lukas P Frenzel, Alessandro Torgovnick, Janica Lea Wiederstein, Claudia Maria Wunderlich, Monika Ortmann, Arlette Paillard, Wilhelm Wößmann, Arndt Borkhardt, Stefan Burdach, Martin-Leo Hansmann, Andreas Rosenwald, Sven Perner, Gita Mall, Wolfram Klapper, Andrea Merseburg, Marcus Krüger, Holger Grüll, Thorsten Persigehl, Frank Thomas Wunderlich, Martin Peifer, Olaf Utermöhlen, Reinhard Büttner, Filippo Beleggia, Hans Christian Reinhardt
The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients...
November 5, 2019: Leukemia
Paula Barros Terraciano, Tuane Alves Garcez, Markus Berger, Isabel Durli, Cristiana Palma Kuhl, Vitória de Oliveira Batista, Raquel de Almeida Schneider, Jaquelline Festa, Emily Pilar, Charles Ferreira, Eduardo Pandolfi Passos, Elizabeth Cirne Lima
OBJECTIVE: The aim of this study was to investigate the efficacy of protocols for mice ovary cryopreservation to compare the differences in Mouse Vasa Homologue expression (a germline cell marker) and ovarian viability after vitrification or slow freezing. METHODS: Female CF1 mice aged 40-45 days were randomly divided into three groups: Control, vitrification or slow freezing. Their ovaries were surgically removed, rinsed in saline solution and cryopreserved. For vitrification, we used a commercial protocol and for slow freeze, we used 1...
November 5, 2019: JBRA Assisted Reproduction
Prabin Upadhyaya, Alessandra Di Serafino, Luca Sorino, Patrizia Ballerini, Marco Marchisio, Laura Pierdomenico, Liborio Stuppia, Ivana Antonucci
BACKGROUND: Bleomycin, etoposide and cisplatin (BEP) are three chemotherapeutic agents widely used individually or in combination with each other or other chemotherapeutic agents in the treatment of various cancers. These chemotherapeutic agents are cytotoxic; hence, along with killing cancerous cells, they also damage stem cell pools in the body, which causes various negative effects on patients. The epigenetic changes due to the individual action of BEP on stem cells are largely unknown...
October 28, 2019: BMC Medical Genomics
Stella Pearson, Baoqiang Guo, Andrew Pierce, Narges Azadbakht, Julie A Brazzatti, Stefano Patassini, Sonia Mulero-Navarro, Stefan Meyer, Christian Flotho, Bruce D Gelb, Anthony D Whetton
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of early childhood with a poor survival rate thus there is a requirement for improved treatment strategies. Induced pluripotent stem cells offer the ability to model disease and develop new treatment strategies. JMML is frequently associated with mutations in PTPN11. Children with Noonan syndrome, a development disorder, have an increased incidence of JMML associated with specific germline mutations in PTPN11. We undertook a proteomic assessment of myeloid cells derived from induced pluripotent stem cells obtained from Noonan syndrome patients with PTPN11 mutations, either associated or not associated with increased incidence of JMML...
October 28, 2019: Journal of Proteome Research
Chichu Xie, Fangming Zhu, Julie Wang, Weizhou Zhang, Joseph A Bellanti, Bin Li, David Brand, Nancy Olsen, Song Guo Zheng
The Cre-LoxP conditional knockout strategy has been used extensively to study gene function in a specific cell-type. In this study, the authors tried to engineer mice in which the Dbc1 gene is conditionally knocked out in Treg cells. Unexpectedly, the conditional Dbc1 allele was completely deleted with a low frequency in some Foxp3 YFP-Cre mice harboring floxed Dbc1 allele under specific settings. It was found that the germline recombination of floxed Dbc1 allele, which caused Dbc1 knock out mice, occurred in the male Foxp3 YFP-Cre mice harboring floxed Dbc1 allele...
October 24, 2019: Cells
Julian Borrow, Sara A Dyer, Susanna Akiki, Michael J Griffiths
Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML). AML with mutated NPM1 is recognised as a separate entity in the World Health Organisation 2016 classification, and carries a relatively favourable prognosis. NPM1 mutations are predominantly 4 bp duplications or insertions in the terminal exon that arise through an unknown mechanism. Here we analyse 2430 NPM1 mutations from 2329 adult and 101 pediatric patients to address their origin. We show that NPM1 mutations display the hallmarks of replication slippage, but lack suitable germline microhomology available for priming...
October 17, 2019: Blood
Manu D Tiwari, Daniela M Zeitler, Gunter Meister, Andreas Wodarz
Stem cells can self-renew and also produce daughter cells destined for differentiation. The precise control of the balance between these two outcomes is essential to ensure tissue homeostasis and to prevent uncontrolled proliferation resulting in tumor formation. As self-renewal and differentiation are likely to be controlled by different gene expression programs, unraveling the underlying gene regulatory networks is crucial for understanding the molecular logic of this system. In this study, we have characterized by next generation RNA sequencing (RNA-seq) the transcriptome of germline stem cell (GSC)-like cells isolated from bag of marbles ( bam ) mutant Drosophila ovaries and compared it to the transcriptome of germ line cells isolated from wild type ovaries...
October 24, 2019: Biology Open
Benjamin Story, Xing Ma, Kazue Ishihara, Hua Li, Kathryn Hall, Allison Peak, Perera Anoja, Jungeun Park, Jeff Haug, Marco Blanchette, Ting Xie
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...
October 2019: Life Science Alliance
Hong Ma, Tomonari Hayama, Crystal Van Dyken, Hayley Darby, Amy Koski, Yeonmi Lee, Nuria Marti Gutierrez, Satsuki Yamada, Ying Li, Michael Andrews, Riffat Ahmed, Dan Liang, Thanasup Gonmanee, Eunju Kang, Mohammed Nasser, Beth Kempton, John Brigande, Trevor J McGill, Andre Terzic, Paula Amato, Shoukhrat Mitalipov
Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here, we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development...
October 17, 2019: Biology of Reproduction
Benjamin Story, Xing Ma, Kazue Ishihara, Hua Li, Kathryn Hall, Allison Peak, Perera Anoja, Jungeun Park, Jeff Haug, Marco Blanchette, Ting Xie
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...
October 2019: Life Science Alliance
Lucie Lanikova, Olga Babosova, Josef T Prchal
Myeloproliferative neoplasms (MPN) are genetically very complex and heterogeneous diseases in which the acquisition of a somatic driver mutation triggers three main myeloid cytokine receptors, and phenotypically expresses as polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The course of the diseases may be influenced by germline predispositions, modifying mutations, their order of acquisition and environmental factors such as aging and inflammation. Deciphering these contributory elements, their mutual interrelationships, and their contribution to MPN pathogenesis brings important insights into the diseases...
October 15, 2019: Genes
Lars Hangartner
Using a transgenic mouse strain expressing the human VH 1-69 germline gene used by many broadly neutralizing antibodies to influenza A virus, Sangesland et al. show that the VH 1-69 gene segment provides the essentials for mounting antibody responses against the conserved hemagglutinin stem epitope.
October 15, 2019: Immunity
August A Allocco, Sheng Chih Jin, Phan Q Duy, Charuta G Furey, Xue Zeng, Weilai Dong, Carol Nelson-Williams, Jason K Karimy, Tyrone DeSpenza, Le T Hao, Benjamin Reeves, Shozeb Haider, Murat Gunel, Richard P Lifton, Kristopher T Kahle
Background: ATP1A3 encodes the α3 subunit of the Na+ /K+ ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, ATP1A3 is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in ATP1A3 have never been associated with any human disease. Atp1a3 deficiency in zebrafish results in hydrocephalus; however, no known association exists between ATP1A3 and human congenital hydrocephalus (CH). Methods: We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel ATP1A3 mutations in a patient with CH...
2019: Frontiers in Cellular Neuroscience
Merrick Pierson Smela, Anastasiya Sybirna, Frederick C K Wong, M Azim Surani
Background: Potentially novel regulators of early human germline development have been identified recently, including SOX15 and SOX17, both of which show specific expression in human primordial germ cells. SOX17 is now known to be a critical specifier of human germ cell identity. There have been suggestions, as yet without evidence, that SOX15 might also play a prominent role. The early human germline is inaccessible for direct study, but an in vitro model of human primordial germ cell-like cell (hPGCLC) specification from human embryonic stem cells (hESCs) has been developed...
2019: Wellcome Open Research
Hoi Ching Suen, Yan Qian, Jinyue Liao, Chun Shui Luk, Wing Tung Lee, Judy Kin Wing Ng, Thomas Ting Hei Chan, Hei Wan Hou, Ingrid Li, Kit Li, Wai-Yee Chan, Bo Feng, Lin Gao, Xiaohua Jiang, Yuen Hang Liu, John A Rudd, Robin Hobbs, Huayu Qi, Tsz Kin Ng, Heather Kayew Mak, Kai Shun Leung, Tin-Lap Lee
Glaucoma is characterized by retinal ganglion cell (RGC) degeneration and is the second leading cause of blindness worldwide. However, current treatments such as eye drop or surgery have limitations and do not target the loss of RGC. Regenerative therapy using embryonic stem cells (ESCs) holds a promising option, but ethical concern hinders clinical applications on human subjects. In this study, we employed spermatogonial stem cells (SSCs) as an alternative source of ESCs for cell-based regenerative therapy in mouse glaucoma model...
October 3, 2019: Stem Cells and Development
Daphna Nachmani, Anne H Bothmer, Silvia Grisendi, Aldo Mele, Dietmar Bothmer, Jonathan D Lee, Emanuele Monteleone, Ke Cheng, Yang Zhang, Assaf C Bester, Alison Guzzetti, Caitlin A Mitchell, Lourdes M Mendez, Olga Pozdnyakova, Paolo Sportoletti, Maria-Paola Martelli, Tom J Vulliamy, Modi Safra, Schraga Schwartz, Lucio Luzzatto, Olivier Bluteau, Jean Soulier, Robert B Darnell, Brunangelo Falini, Inderjeet Dokal, Keisuke Ito, John G Clohessy, Pier Paolo Pandolfi
RNA modifications are emerging as key determinants of gene expression. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link ribosomal RNA 2'-O-methylation (2'-O-Me) to the etiology of dyskeratosis congenita. We identify nucleophosmin (NPM1) as an essential regulator of 2'-O-Me on rRNA by directly binding C/D box small nucleolar RNAs, thereby modulating translation. We demonstrate the importance of 2'-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell maintenance, and show that Npm1 inactivation in adult hematopoietic stem cells results in bone marrow failure...
September 30, 2019: Nature Genetics
Rajesh Ranjan, Jonathan Snedeker, Xin Chen
Many stem cells utilize asymmetric cell division (ACD) to produce a self-renewed stem cell and a differentiating daughter cell. How non-genic information could be inherited differentially to establish distinct cell fates is not well understood. Here, we report a series of spatiotemporally regulated asymmetric components, which ensure biased sister chromatid attachment and segregation during ACD of Drosophila male germline stem cells (GSCs). First, sister centromeres are differentially enriched with proteins involved in centromere specification and kinetochore function...
September 25, 2019: Cell Stem Cell
Paola Cruz-Tapias, Philippe Robin, Julien Pontis, Laurence Del Maestro, Slimane Ait-Si-Ali
SETDB1 (SET Domain Bifurcated histone lysine methyltransferase 1) is a key lysine methyltransferase (KMT) required in embryonic stem cells (ESCs), where it silences transposable elements and DNA repeats via histone H3 lysine 9 tri-methylation (H3K9me3), independently of DNA methylation. The H3K9 methylation reader M-Phase Phosphoprotein 8 (MPP8) is highly expressed in ESCs and germline cells. Although evidence of a cooperation between H3K9 KMTs and MPP8 in committed cells has emerged, the interplay between H3K9 methylation writers and MPP8 in ESCs remains elusive...
September 25, 2019: Genes
Ngoc Tung Tran, Thomas Sommermann, Robin Graf, Janine Trombke, Jenniffer Pempe, Kerstin Petsch, Ralf Kühn, Klaus Rajewsky, Van Trung Chu
Mutations accumulating in hematopoietic stem and progenitor cells (HSPCs) during development can cause severe hematological disorders. Modeling these mutations in mice is essential for understanding their functional consequences. Here, we describe an efficient CRISPR/Cas9-based system to knock in and repair genes in mouse HSPCs. CRISPR/Cas9 ribonucleoproteins, in combination with recombinant adeno-associated virus (rAAV)-DJ donor templates, led to gene knockin efficiencies of up to 30% in the Lmnb1 and Actb loci of mouse HSPCs in vitro...
September 24, 2019: Cell Reports
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