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1.
Nat Commun ; 12(1): 5056, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417458

RESUMO

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a-/- melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.


Assuntos
Epigênese Genética , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fator de Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica , Micrometástase de Neoplasia , Ligação Proteica , Carga Tumoral
2.
Nat Commun ; 10(1): 2192, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097699

RESUMO

The transcription factor Yin Yang 1 (YY1) plays an important role in human disease. It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. Here, we show that Yy1 controls murine cerebral cortex development in a stage-dependent manner. By regulating a wide range of metabolic pathways and protein translation, Yy1 maintains proliferation and survival of neural progenitor cells (NPCs) at early stages of brain development. Despite its constitutive expression, however, the dependence on Yy1 declines over the course of corticogenesis. This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Thus, our study unravels a novel role for Yy1 as a stage-dependent regulator of brain development and shows that biosynthetic demands of NPCs dynamically change throughout development.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células-Tronco Neurais/fisiologia , Fator de Transcrição YY1/fisiologia , Animais , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Embrião de Mamíferos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Inativação de Genes , Redes e Vias Metabólicas/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Animais , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo
3.
J Clin Invest ; 129(7): 2702-2716, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039140

RESUMO

The development of metastatic melanoma is thought to require the dynamic shifting of neoplastic cells between proliferative and invasive phenotypes. Contrary to this conventional "phenotype switching" model, we now show that disease progression can involve malignant melanoma cells simultaneously displaying proliferative and invasive properties. Using a genetic mouse model of melanoma in combination with in vitro analyses of melanoma cell lines, we found that conditional deletion of the downstream signaling molecule Smad4, which abrogates all canonical TGF-ß signaling, indeed inhibits both tumor growth and metastasis. Conditional deletion of the inhibitory signaling factor Smad7, however, generated cells that are both highly invasive and proliferative, indicating that invasiveness is compatible with a high proliferation rate. In fact, conditional Smad7 deletion led to sustained melanoma growth and at the same time promoted massive metastasis formation, a result consistent with data indicating that low SMAD7 levels in patient tumors are associated with a poor survival. Our findings reveal that modulation of SMAD7 levels can overcome the need for phenotype switching during tumor progression and may thus represent a novel therapeutic target in metastatic disease.


Assuntos
Melanoma/metabolismo , Transdução de Sinais , Proteína Smad7/metabolismo , Animais , Intervalo Livre de Doença , Humanos , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Knockout , Invasividade Neoplásica , Metástase Neoplásica , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad7/genética , Taxa de Sobrevida
4.
Cell Stem Cell ; 24(4): 637-653.e9, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951662

RESUMO

Increasing evidence suggests that cancer cells highjack developmental programs for disease initiation and progression. Melanoma arises from melanocytes that originate during development from neural crest stem cells (NCSCs). Here, we identified the transcription factor Yin Yang 1 (Yy1) as an NCSCs regulator. Conditional deletion of Yy1 in NCSCs resulted in stage-dependent hypoplasia of all major neural crest derivatives due to decreased proliferation and increased cell death. Moreover, conditional ablation of one Yy1 allele in a melanoma mouse model prevented tumorigenesis, indicating a particular susceptibility of melanoma cells to reduced Yy1 levels. Combined RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and untargeted metabolomics demonstrated that YY1 governs multiple metabolic pathways and protein synthesis in both NCSCs and melanoma. In addition to directly regulating a metabolic gene set, YY1 can act upstream of MITF/c-MYC as part of a gene regulatory network controlling metabolism. Thus, both NCSC development and melanoma formation depend on an intricate YY1-controlled metabolic program.


Assuntos
Melanoma/metabolismo , Melanoma/patologia , Crista Neural/citologia , Crista Neural/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Fator de Transcrição YY1/deficiência
5.
Cell Stem Cell ; 16(3): 314-22, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25748934

RESUMO

The neural crest (NC) is an embryonic stem/progenitor cell population that generates a diverse array of cell lineages, including peripheral neurons, myelinating Schwann cells, and melanocytes, among others. However, there is a long-standing controversy as to whether this broad developmental perspective reflects in vivo multipotency of individual NC cells or whether the NC is comprised of a heterogeneous mixture of lineage-restricted progenitors. Here, we resolve this controversy by performing in vivo fate mapping of single trunk NC cells both at premigratory and migratory stages using the R26R-Confetti mouse model. By combining quantitative clonal analyses with definitive markers of differentiation, we demonstrate that the vast majority of individual NC cells are multipotent, with only few clones contributing to single derivatives. Intriguingly, multipotency is maintained in migratory NC cells. Thus, our findings provide definitive evidence for the in vivo multipotency of both premigratory and migrating NC cells in the mouse.


Assuntos
Antígenos de Diferenciação/metabolismo , Linhagem da Célula/fisiologia , Movimento Celular/fisiologia , Células-Tronco Multipotentes/metabolismo , Crista Neural/embriologia , Crista Neural/metabolismo , Animais , Camundongos , Camundongos Transgênicos , Células-Tronco Multipotentes/citologia , Crista Neural/citologia
6.
Cell Stem Cell ; 15(4): 397-399, 2014 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-25280213

RESUMO

Aberrant neural crest (NC) development is at the origin of many congenital diseases. Given the limitations in human NC cell isolation and expansion, the development of new strategies for NC generation is crucial. In this issue of Cell Stem Cell, Kim et al. (2014) report the direct reprogramming of postnatal fibroblasts into multipotent NC cells.


Assuntos
Reprogramação Celular , Células-Tronco Multipotentes/citologia , Crista Neural/citologia , Fatores de Transcrição SOXE/metabolismo , Animais , Humanos
7.
Development ; 141(4): 867-77, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24496623

RESUMO

The emergence of craniofacial skeletal elements, and of the jaw in particular, was a crucial step in the evolution of higher vertebrates. Most facial bones and cartilage are generated during embryonic development by cranial neural crest cells, while an osteochondrogenic fate is suppressed in more posterior neural crest cells. Key players in this process are Hox genes, which suppress osteochondrogenesis in posterior neural crest derivatives. How this specific pattern of osteochondrogenic competence is achieved remains to be elucidated. Here we demonstrate that Hox gene expression and osteochondrogenesis are controlled by epigenetic mechanisms. Ezh2, which is a component of polycomb repressive complex 2 (PRC2), catalyzes trimethylation of lysine 27 in histone 3 (H3K27me3), thereby functioning as transcriptional repressor of target genes. Conditional inactivation of Ezh2 does not interfere with localization of neural crest cells to their target structures, neural development, cell cycle progression or cell survival. However, loss of Ezh2 results in massive derepression of Hox genes in neural crest cells that are usually devoid of Hox gene expression. Accordingly, craniofacial bone and cartilage formation is fully prevented in Ezh2 conditional knockout mice. Our data indicate that craniofacial skeleton formation in higher vertebrates is crucially dependent on epigenetic regulation that keeps in check inhibitors of an osteochondrogenic differentiation program.


Assuntos
Cartilagem/embriologia , Condrogênese/fisiologia , Epigênese Genética/fisiologia , Ossos Faciais/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Crista Neural/fisiologia , Osteogênese/fisiologia , Complexo Repressor Polycomb 2/metabolismo , Azul Alciano , Animais , Antraquinonas , Imunoprecipitação da Cromatina , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste , Citometria de Fluxo , Galactosídeos , Regulação da Expressão Gênica no Desenvolvimento/genética , Histonas/metabolismo , Imuno-Histoquímica , Indóis , Camundongos , Camundongos Transgênicos , Análise em Microsséries , Crista Neural/metabolismo , Complexo Repressor Polycomb 2/genética , Reação em Cadeia da Polimerase em Tempo Real
8.
PLoS One ; 6(6): e20914, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21698063

RESUMO

BACKGROUND: Human pluripotent stem cells have the ability to generate all cell types present in the adult organism, therefore harboring great potential for the in vitro study of differentiation and for the development of cell-based therapies. Nonetheless their use may prove challenging as incomplete differentiation of these cells might lead to tumoregenicity. Interestingly, many cancer types have been reported to display metabolic modifications with features that might be similar to stem cells. Understanding the metabolic properties of human pluripotent stem cells when compared to their differentiated counterparts can thus be of crucial importance. Furthermore recent data has stressed distinct features of different human pluripotent cells lines, namely when comparing embryo-derived human embryonic stem cells (hESCs) and induced pluripotent stem cells (IPSCs) reprogrammed from somatic cells. METHODOLOGY/PRINCIPAL FINDINGS: We compared the energy metabolism of hESCs, IPSCs, and their somatic counterparts. Focusing on mitochondria, we tracked organelle localization and morphology. Furthermore we performed gene expression analysis of several pathways related to the glucose metabolism, including glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA) cycle. In addition we determined oxygen consumption rates (OCR) using a metabolic extracellular flux analyzer, as well as total intracellular ATP levels by high performance liquid chromatography (HPLC). Finally we explored the expression of key proteins involved in the regulation of glucose metabolism. CONCLUSIONS/FINDINGS: Our results demonstrate that, although the metabolic signature of IPSCs is not identical to that of hESCs, nonetheless they cluster with hESCs rather than with their somatic counterparts. ATP levels, lactate production and OCR revealed that human pluripotent cells rely mostly on glycolysis to meet their energy demands. Furthermore, our work points to some of the strategies which human pluripotent stem cells may use to maintain high glycolytic rates, such as high levels of hexokinase II and inactive pyruvate dehydrogenase (PDH).


Assuntos
Diferenciação Celular , Metabolismo Energético , Células-Tronco Pluripotentes/metabolismo , Western Blotting , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Consumo de Oxigênio , Células-Tronco Pluripotentes/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução Genética
9.
PLoS One ; 5(10): e13410, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20976220

RESUMO

BACKGROUND: Induced pluripotent stem (iPS) cells have the capability to undergo self-renewal and differentiation into all somatic cell types. Since they can be produced through somatic cell reprogramming, which uses a defined set of transcription factors, iPS cells represent important sources of patient-specific cells for clinical applications. However, before these cells can be used in therapeutic designs, it is essential to understand their genetic stability. METHODOLOGY/PRINCIPAL FINDINGS: Here, we describe DNA damage responses in human iPS cells. We observe hypersensitivity to DNA damaging agents resulting in rapid induction of apoptosis after γ-irradiation. Expression of pluripotency factors does not appear to be diminished after irradiation in iPS cells. Following irradiation, iPS cells activate checkpoint signaling, evidenced by phosphorylation of ATM, NBS1, CHEK2, and TP53, localization of ATM to the double strand breaks (DSB), and localization of TP53 to the nucleus of NANOG-positive cells. We demonstrate that iPS cells temporary arrest cell cycle progression in the G(2) phase of the cell cycle, displaying a lack of the G(1)/S cell cycle arrest similar to human embryonic stem (ES) cells. Furthermore, both cell types remove DSB within six hours of γ-irradiation, form RAD51 foci and exhibit sister chromatid exchanges suggesting homologous recombination repair. Finally, we report elevated expression of genes involved in DNA damage signaling, checkpoint function, and repair of various types of DNA lesions in ES and iPS cells relative to their differentiated counterparts. CONCLUSIONS/SIGNIFICANCE: High degrees of similarity in DNA damage responses between ES and iPS cells were found. Even though reprogramming did not alter checkpoint signaling following DNA damage, dramatic changes in cell cycle structure, including a high percentage of cells in the S phase, increased radiosensitivity and loss of DNA damage-induced G(1)/S cell cycle arrest, were observed in stem cells generated by induced pluripotency.


Assuntos
Dano ao DNA , Células-Tronco Embrionárias/citologia , Células-Tronco Pluripotentes/citologia , Western Blotting , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Linhagem Celular , Reparo do DNA , Células-Tronco Embrionárias/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Microscopia Confocal , Fosforilação , Células-Tronco Pluripotentes/metabolismo , Reação em Cadeia da Polimerase
10.
Cell Reprogram ; 12(3): 263-73, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20698768

RESUMO

Deciding to exit pluripotency and undergo differentiation is of singular importance for pluripotent cells, including embryonic stem cells (ESCs). The molecular mechanisms for these decisions to differentiate, as well as reversing those decisions during induced pluripotency (iPS), have focused largely on transcriptomic controls. Here, we explore the role of translational control for the maintenance of pluripotency and the decisions to differentiate. Global protein translation is significantly reduced in hESCs compared to their differentiated progeny. Furthermore, p70 S6K activation is restricted in hESCs compared to differentiated fibroblast-like cells. Disruption of p70 S6K-mediated translation by rapamycin or siRNA knockdown in undifferentiated hESCs does not alter cell viability or expression of the pluripotency markers Oct4 and Nanog. However, expression of constitutively active p70 S6K, but not wild-type p70 S6K, induces differentiation. Additionally, hESCs exhibit high levels of the mTORC1/p70 S6K inhibitory complex TSC1/TSC2 and preferentially express more rapamycin insensitive mTORC2 compared to differentiated cells. siRNA-mediated knockdown of both TSC2 and Rictor elevates p70 S6K activation and induces differentiation of hESCs. These results suggest that hESCs tightly regulate mTORC1/p70 S6K-mediated protein translation to maintain a pluripotent state as well as implicate a novel role for protein synthesis as a driving force behind hESC differentiation.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/citologia , Células-Tronco Pluripotentes/citologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/fisiologia , Células-Tronco Embrionárias/efeitos dos fármacos , Ativação Enzimática , Humanos , Microscopia Eletrônica de Transmissão , Células-Tronco Pluripotentes/efeitos dos fármacos , Interferência de RNA , Sirolimo/farmacologia
11.
Stem Cells ; 27(8): 1822-35, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19544417

RESUMO

Human embryonic stem (ES) cells are highly sensitive to environmental insults including DNA damaging agents, responding with high levels of apoptosis. To understand the response of human ES cells to DNA damage, we investigated the function of the ataxia telangiectasia mutated (ATM) DNA damage signaling pathway in response to gamma-irradiation. Here, we demonstrate for the first time in human ES cells that ATM kinase is phosphorylated and properly localized to the sites of DNA double-strand breaks within 15 minutes of irradiation. Activation of ATM kinase resulted in phosphorylation of its downstream targets: Chk2, p53, and Nbs1. In contrast to murine ES cells, Chk2 and p53 were localized to the nucleus of irradiated human ES cells. We further show that irradiation resulted in a temporary arrest of the cell cycle at the G(2), but not G(1), phase. Human ES cells resumed cycling approximately 16 hours after irradiation, but had a fourfold higher incidence of aberrant mitotic figures compared to nonirradiated cells. Finally, we demonstrate an essential role of ATM in establishing G(2) arrest since inhibition with the ATM-specific inhibitor KU55933 resulted in abolishment of G(2) arrest, evidenced by an increase in the number of cycling cells 2 hours after irradiation. In summary, these results indicate that human ES cells activate the DNA damage checkpoint, resulting in an ATM-dependent G(2) arrest. However, these cells re-enter the cell cycle with prominent mitotic spindle defects.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/efeitos da radiação , Fase G1/efeitos da radiação , Fase G2/efeitos da radiação , Células-Tronco Pluripotentes/efeitos da radiação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Proteínas Mutadas de Ataxia Telangiectasia , Western Blotting , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta à Radiação , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Fase G1/genética , Fase G2/genética , Raios gama , Humanos , Imuno-Histoquímica , Microscopia Confocal , Fosforilação , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/metabolismo , Radiação Ionizante , Transdução de Sinais/efeitos da radiação , Proteínas Supressoras de Tumor/metabolismo
12.
Hum Reprod Update ; 15(5): 553-72, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19414527

RESUMO

BACKGROUND: Mitochondria are multitasking organelles involved in ATP synthesis, reactive oxygen species (ROS) production, calcium signalling and apoptosis; and mitochondrial defects are known to cause physiological dysfunction, including infertility. The goal of this review was to identify and discuss common themes in mitochondrial function related to mammalian reproduction. METHODS: The scientific literature was searched for studies reporting on the several aspects of mitochondrial activity in mammalian testis, sperm, oocytes, early embryos and embryonic stem cells. RESULTS: ATP synthesis and ROS production are the most discussed aspects of mitochondrial function. Metabolic shifts from mitochondria-produced ATP to glycolysis occur at several stages, notably during gametogenesis and early embryo development, either reflecting developmental switches or substrate availability. The exact role of sperm mitochondria is especially controversial. Mitochondria-generated ROS function in signalling but are mostly described when produced under pathological conditions. Mitochondria-based calcium signalling is primarily important in embryo activation and embryonic stem cell differentiation. Besides pathologically triggered apoptosis, mitochondria participate in apoptotic events related to the regulation of spermatogonial cell number, as well as gamete, embryo and embryonic stem cell quality. Interestingly, data from knock-out (KO) mice is not always straightforward in terms of expected phenotypes. Finally, recent data suggests that mitochondrial activity can modulate embryonic stem cell pluripotency as well as differentiation into distinct cellular fates. CONCLUSIONS: Mitochondria-based events regulate different aspects of reproductive function, but these are not uniform throughout the several systems reviewed. Low mitochondrial activity seems a feature of 'stemness', being described in spermatogonia, early embryo, inner cell mass cells and embryonic stem cells.


Assuntos
Mitocôndrias/fisiologia , Reprodução/fisiologia , Trifosfato de Adenosina/biossíntese , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Apoptose , Sinalização do Cálcio , Embrião de Mamíferos/fisiologia , Células-Tronco Embrionárias/fisiologia , Células-Tronco Embrionárias/ultraestrutura , Metabolismo Energético , Feminino , Células Germinativas/fisiologia , Células Germinativas/ultraestrutura , Gônadas/citologia , Gônadas/fisiologia , Humanos , Masculino , Camundongos , Mitocôndrias/ultraestrutura , Modelos Biológicos , Gravidez , Espécies Reativas de Oxigênio/metabolismo , Esteroides/biossíntese
13.
Fertil Steril ; 87(3): 572-83, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17118365

RESUMO

OBJECTIVE: To directly compare distinct assays proposed to monitor human sperm quality and possibly preselect sperm populations for assisted reproductive technology (ART). DESIGN: Analysis of human sperm sample quality using several methodologies. SETTING: Academic and clinical institutions. PATIENT(S): Samples from consenting patients undergoing routine semen analysis or ART. INTERVENTIONS: Human sperm samples were analyzed in terms of World Health Organization parameters and processed for annexin V, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling of DNA (TUNEL), and the sperm-ubiquitin tag immunoassay (SUTI). Samples were analyzed both by flow cytometry and fluorescence microscopy. MAIN OUTCOME MEASURE(S): Correlations among apoptotic markers (outer leaflet phosphatidylserine exposure, membrane integrity, and DNA fragmentation), external ubiquitination, and semen parameters in human spermatozoa. RESULT(S): Nonviable sperm, TUNEL-positive cells, and ubiquitin fluorescence intensity means inversely correlate with semen parameters. Apoptotic markers do not correlate with sperm surface ubiquitination. Normozoospermic samples have a higher number of viable cells and lower DNA fragmentation compared with samples with abnormal parameters. Nonviable sperm are more prevalent in samples with low counts and poor morphology but not low motility. Not all sperm with morphologic abnormalities present surface ubiquitination. CONCLUSION(S): Sperm quality is inversely correlated with lack of viability, DNA fragmentation, and ubiquitin fluorescence intensity means. However, none of the apoptotic markers correlate with ubiquitin labeling. Elimination of defective sperm cells prior to ART using surface markers (annexin V, ubiquitin) seems unwarranted at this stage.


Assuntos
Apoptose/fisiologia , Espermatozoides/fisiologia , Anexina A5/análise , Sobrevivência Celular , Fragmentação do DNA , Citometria de Fluxo , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Microscopia de Fluorescência , Fosfatidilserinas/metabolismo , Pirimidinonas , Motilidade Espermática , Espermatozoides/química , Espermatozoides/imunologia , Ubiquitina/análise
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