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400 results on '"Edenhofer, Frank"'

56. CRISPR/Cas9-edited PKP2 knock-out (JMUi001-A-2) and DSG2 knock-out (JMUi001-A-3) iPSC lines as an isogenic human model system for arrhythmogenic cardiomyopathy (ACM)

Author

Janz, Anna, Zink, Miriam, Cirnu, Alexandra, Hartleb, Annika, Albrecht, Christina, Rost, Simone, Klopocki, Eva, Günther, Katharina, Edenhofer, Frank, Ergün, Süleyman, and Gerull, Brenda

Subjects
Desmoglein 2, QH301-705.5, Induced Pluripotent Stem Cells, Mutation, Humans, Myocytes, Cardiac, ddc:610, Biology (General), CRISPR-Cas Systems, Cardiomyopathies, Plakophilins
Abstract

Arrhythmogenic cardiomyopathy (ACM) is characterized by fibro-fatty replacement of the myocardium, heart failure and life-threatening ventricular arrhythmias. Causal mutations were identified in genes encoding for proteins of the desmosomes, predominantly plakophilin-2 (PKP2) and desmoglein-2 (DSG2). We generated gene-edited knock-out iPSC lines for PKP2 (JMUi001-A-2) and DSG2 (JMUi001-A-3) using the CRISPR/Cas9 system in a healthy control iPSC background (JMUi001-A). Stem cell-like morphology, robust expression of pluripotency markers, embryoid body formation and normal karyotypes confirmed the generation of high quality iPSCs to provide a novel isogenic human in vitro model system mimicking ACM when differentiated into cardiomyocytes.

Published
2021

57. Generation of induced pluripotent stem cell (iPSC) lines carrying a heterozygous (UKWMPi002-A-1) and null mutant knockout (UKWMPi002-A-2) of Cadherin 13 associated with neurodevelopmental disorders using CRISPR/Cas9

Author

Vitale, Maria Rosaria, primary, Zöller, Johanna Eva Maria, additional, Jansch, Charline, additional, Janz, Anna, additional, Edenhofer, Frank, additional, Klopocki, Eva, additional, van den Hove, Daniel, additional, Vanmierlo, Tim, additional, Rivero, Olga, additional, Nadif Kasri, Nael, additional, Ziegler, Georg Christoph, additional, and Lesch, Klaus-Peter, additional

Published
2021
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59. Energy Metabolism Disturbances in Cell Models of PARK2 CNV Carriers with ADHD

Author

Palladino, Viola Stella, primary, Chiocchetti, Andreas G., additional, Frank, Lukas, additional, Haslinger, Denise, additional, McNeill, Rhiannon, additional, Radtke, Franziska, additional, Till, Andreas, additional, Haupt, Simone, additional, Brüstle, Oliver, additional, Günther, Katharina, additional, Edenhofer, Frank, additional, Hoffmann, Per, additional, Reif, Andreas, additional, and Kittel-Schneider, Sarah, additional

Published
2020
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61. Generation of two patient-derived iPSC lines from siblings (LIBUCi001-A and LIBUCi002-A) and a genetically modified iPSC line (JMUi001-A-1) to mimic dilated cardiomyopathy with ataxia (DCMA) caused by a homozygous DNAJC19 mutation

Author

Janz, Anna, primary, Chen, Ruping, additional, Regensburger, Martina, additional, Ueda, Yuichiro, additional, Rost, Simone, additional, Klopocki, Eva, additional, Günther, Katharina, additional, Edenhofer, Frank, additional, Duff, Henry J., additional, Ergün, Süleyman, additional, and Gerull, Brenda, additional

Published
2020
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64. Development of a bioreactor system for pre-endothelialized cardiac patch generation with enhanced viscoelastic properties by combined collagen I compression and stromal cell culture

Author

Krziminski, Carolin, Kammann, Sebastian, Hansmann, Jan, Edenhofer, Frank, Dandekar, Gudrun, Walles, Heike, Leistner, Marcus, and Publica

Subjects
cardiac tissue engineering, scaffold prevascularization, left atrial appendage, plastic compression
Abstract

Treatment of terminal heart failure still poses a significant clinical problem. Cardiac tissue engineering could offer autologous solutions for the replacement of nonfunctional myocardial tissue. So far, soft matrix construction and missing large-scale prevascularization prevented the application of sizeable cardiac repair patches. We developed a novel bioreactor system for semi-automatic compression of a collagen I hydrogel applying 16 times higher pressure than in previous studies. Resistance towards compression stress was investigated for multiple cardiac-related cell types. For scaffold prevascuarization, a tubular cavity was imprinted during the compaction process. Primary cardiac-derived endothelial cells (ECs) were isolated from human left atrial appendages (HLAAs) and characterized by fluorescence-activated cell sorting (FACS) and immunocytology. EC were then seeded into the preformed channel with dermal fibroblasts as interstitial cell component of the fully cellularized patch. After 8 days of constant perfusion culture within the same bioreactor, scaffold dynamic modulus and cell viability were analyzed. Endothelial proliferation and vessel maturation were examined by immunohistochemistry and transmission electron microscopy. Our design allowed for scaffold production and dynamic culture in a one-stop-shop model. Enhanced compression and cell-mediated matrix remodeling induced a significant increase in scaffold stiffness while ensuring excellent cell survival. For the first time, we could isolate HLAA-derived EC with proliferative potential. ECs within the central channel proliferated during flow culture, continuously expressing endothelial markers (CD31) and displaying basal membrane synthesis (collagen IV, ultrastructural analysis). After 7 days of culture, a complete endothelial monolayer could be observed. Covering cells aligned themselves in flow direction and developed mature cell-cell contacts.

Published
2020

66. ADHD‐associated PARK2copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient‐derived cell lines

Author

Radtke, Franziska, Palladino, Viola Stella, McNeill, Rhiannon V., Chiocchetti, Andreas G., Haslinger, Denise, Leyh, Matthias, Gersic, Danijel, Frank, Markus, Grünewald, Lena, Klebe, Stephan, Brüstle, Oliver, Günther, Katharina, Edenhofer, Frank, Kranz, Thorsten M., Reif, Andreas, and Kittel‐Schneider, Sarah

Abstract

Recent studies show an association of Parkin RBR E3 ubiquitin protein ligase (PARK2) copy number variations (CNVs) with attention deficit hyperactivity disorder (ADHD). The aim of our pilot study to investigate gene expression associated with PARK2CNVs in human‐derived cellular models. We investigated gene expression in fibroblasts, hiPSC and dopaminergic neurons (DNs) of ADHD PARK2deletion and duplication carriers by qRT PCR compared with healthy and ADHD cell lines without PARK2CNVs. The selected 10 genes of interest were associated with oxidative stress response (TP53, NQO1,and NFE2L2), ubiquitin pathway (UBE3A, UBB, UBC,and ATXN3) and with a function in mitochondrial quality control (PINK1, MFN2,and ATG5). Additionally, an exploratory RNA bulk sequencing analysis in DNs was conducted. Nutrient deprivation as a supplementary deprivation stress paradigm was used to enhance potential genotype effects. At baseline, in fibroblasts, hiPSC, and DNs, there was no significant difference in gene expression after correction for multiple testing. After nutrient deprivation in fibroblasts NAD(P)H‐quinone‐dehydrogenase 1 (NQO1) expression was significantly increased in PARK2CNV carriers. In a multivariate analysis, ubiquitin C (UBC) was significantly upregulated in fibroblasts of PARK2CNV carriers. RNA sequencing analysis of DNs showed the strongest significant differential regulation in Neurontin (NNAT) at baseline and after nutrient deprivation. Our preliminary results suggest differential gene expression in pathways associated with oxidative stress, ubiquitine‐proteasome, immunity, inflammation, cell growth, and differentiation, excitation/inhibition modulation, and energy metabolism in PARK2CNV carriers compared to wildtype healthy controls and ADHD patients.

Published
2022
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68. Energy Metabolism Disturbances in Cell Models of PARK2 CNV Carriers with ADHD

Author

Palladino, Viola Stella, Chiocchetti, Andreas G., Frank, Lukas, Haslinger, Denise, McNeill, Rhiannon, Radtke, Franziska, Till, Andreas, Haupt, Simone, Bruestle, Oliver, Guenther, Katharina, Edenhofer, Frank, Hoffmann, Per, Reif, Andreas, Kittel-Schneider, Sarah, Palladino, Viola Stella, Chiocchetti, Andreas G., Frank, Lukas, Haslinger, Denise, McNeill, Rhiannon, Radtke, Franziska, Till, Andreas, Haupt, Simone, Bruestle, Oliver, Guenther, Katharina, Edenhofer, Frank, Hoffmann, Per, Reif, Andreas, and Kittel-Schneider, Sarah

Abstract

The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.

Published
2020

69. Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile

Author

Kim, Yongsung, Zheng, Xinde, Ansari, Zoya, Bunnell, Mark C., Herdy, Joseph R., Traxler, Larissa, Lee, Hyungjun, Paquola, Apua C.M., Blithikioti, Chrysanthi, Ku, Manching, Schlachetzki, Johannes C.M., Winkler, Jürgen, Edenhofer, Frank, Glass, Christopher K., Paucar, Andres A., Jaeger, Baptiste N., Pham, Son, Boyer, Leah, Campbell, Benjamin C., Hunter, Tony, Mertens, Jerome, and Gage, Fred H.

Published
2018
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71. Monodispersity of recombinant Cre recombinase correlates with its effectiveness in vivo

Author

Edenhofer Frank, Ossolengo Giuseppe, Aliprandi Marisa, Capasso Paola, and de Marco Ario

Subjects
Biotechnology, TP248.13-248.65
Abstract

Abstract Background Cre recombinase is a common reagent used for the in vivo on/off switching of the expression of target genes flanked by loxP sites. In particular, recombinant TAT-Cre fusion constructs purified from bacteria have been used to promote the cell uptake of the enzyme. However, the recovery of active TAT-Cre remains a demanding process and its specific activity varies significantly among batches, making difficult data comparison. Results We noticed a strong correlation between recombinase activity and enzyme monodispersity. The existence of such correlation enabled us to indirectly monitor the TAT-Cre recombinase activity during the multi-step purification process by measuring its monodispersity, a parameter detectable by means of a spectrofluorimetric assay that allows the calculation of the Aggregation Index (AI) in an easy and rapid way. AI values were recorded after each purification passage to identify the critical steps and to choose optimal alternatives for chromatographic conditions, desalting procedures, and protocols for bacterial endotoxin removal. Furthermore, the effect of metal ions and temperature on TAT-Cre aggregation and inactivation was characterized in vitro. Finally, we optimized the enzyme delivery protocol in vivo by following the accumulation tuning of the reporter protein β-catenin. Conclusion A rational purification protocol for TAT-Cre has been developed by choosing the options that minimize the enzyme aggregation. Our data suggest that AI measurement should support the optimization of any protocol aiming at the recovery of monodispersed protein.

Published
2009
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73. Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium Authors

Author

Popp, Bernt, primary, Krumbiegel, Mandy, additional, Grosch, Janina, additional, Sommer, Annika, additional, Uebe, Steffen, additional, Kohl, Zacharias, additional, Plötz, Sonja, additional, Farrell, Michaela, additional, Trautmann, Udo, additional, Kraus, Cornelia, additional, Ekici, Arif B., additional, Asadollahi, Reza, additional, Regensburger, Martin, additional, Günther, Katharina, additional, Rauch, Anita, additional, Edenhofer, Frank, additional, Winkler, Jürgen, additional, Winner, Beate, additional, and Reis, André, additional

Published
2018
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74. Generation of a human induced pluripotent stem cell (iPSC) line from a 51-year-old female with attention-deficit/hyperactivity disorder (ADHD) carrying a duplication of SLC2A3

Author

Jansch, Charline, primary, Günther, Katharina, additional, Waider, Jonas, additional, Ziegler, Georg C., additional, Forero, Andrea, additional, Kollert, Sina, additional, Svirin, Evgeniy, additional, Pühringer, Dirk, additional, Kwok, Chee Keong, additional, Ullmann, Reinhard, additional, Maierhofer, Anna, additional, Flunkert, Julia, additional, Haaf, Thomas, additional, Edenhofer, Frank, additional, and Lesch, Klaus-Peter, additional

Published
2018
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76. Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium

Author

Popp, Bernt; https://orcid.org/0000-0002-3679-1081, Krumbiegel, Mandy, Grosch, Janina, Sommer, Annika, Uebe, Steffen, Kohl, Zacharias; https://orcid.org/0000-0002-4147-8866, Plötz, Sonja, Farrell, Michaela, Trautmann, Udo, Kraus, Cornelia, Ekici, Arif B; https://orcid.org/0000-0001-6099-7066, Asadollahi, Reza; https://orcid.org/0000-0002-1497-0564, Regensburger, Martin; https://orcid.org/0000-0002-2172-7386, Günther, Katharina, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Edenhofer, Frank, Winkler, Jürgen, Winner, Beate, Reis, André; https://orcid.org/0000-0002-6301-6363, Popp, Bernt; https://orcid.org/0000-0002-3679-1081, Krumbiegel, Mandy, Grosch, Janina, Sommer, Annika, Uebe, Steffen, Kohl, Zacharias; https://orcid.org/0000-0002-4147-8866, Plötz, Sonja, Farrell, Michaela, Trautmann, Udo, Kraus, Cornelia, Ekici, Arif B; https://orcid.org/0000-0001-6099-7066, Asadollahi, Reza; https://orcid.org/0000-0002-1497-0564, Regensburger, Martin; https://orcid.org/0000-0002-2172-7386, Günther, Katharina, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Edenhofer, Frank, Winkler, Jürgen, Winner, Beate, and Reis, André; https://orcid.org/0000-0002-6301-6363

Abstract

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.

Published
2018

77. BMP/SMAD Pathway Promotes Neurogenesis of Midbrain Dopaminergic NeuronsIn Vivoand in Human Induced Pluripotent and Neural Stem Cells

Author

Jovanovic, Vukasin M., primary, Salti, Ahmad, additional, Tilleman, Hadas, additional, Zega, Ksenija, additional, Jukic, Marin M., additional, Zou, Hongyan, additional, Friedel, Roland H., additional, Prakash, Nilima, additional, Blaess, Sandra, additional, Edenhofer, Frank, additional, and Brodski, Claude, additional

Published
2018
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80. Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain

Author

Forero, Andrea, primary, Rivero, Olga, additional, Wäldchen, Sina, additional, Ku, Hsing-Ping, additional, Kiser, Dominik P., additional, Gärtner, Yvonne, additional, Pennington, Laura S., additional, Waider, Jonas, additional, Gaspar, Patricia, additional, Jansch, Charline, additional, Edenhofer, Frank, additional, Resink, Thérèse J., additional, Blum, Robert, additional, Sauer, Markus, additional, and Lesch, Klaus-Peter, additional

Published
2017
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81. Combination of In Situ Lcn2pRNA-RNAi Nanotherapeutics and iNSC Transplantation Ameliorates Experimental SCI in Mice

Author

Braga, Alice, Bandiera, Sara, Verheyen, Jeroen, Hamel, Regan, Rutigliani, Carola, Edenhofer, Frank, Smith, Jayden Aaron, and Pluchino, Stefano

Abstract

Spinal cord injury (SCI) is a debilitating neurological condition characterized by different cellular and molecular mechanisms that interplay in exacerbating the progression of the pathology. No fully restorative therapies are yet available, and it is thus becoming recognized that combinatorial approaches aimed at addressing different aspects of SCI will likely results in greater functional outcomes. Here we employed packaging RNA-mediated RNA interference (pRNA-RNAi) nanotherapeutics to downregulate in situthe expression of lipocalin 2(Lcn2), a known mediator of neuroinflammation and autocrine mediator of reactive astrogliosis, and to create a more amenable niche for the subsequent transplantation of induced neural stem cells (iNSCs). To our knowledge, this is the first approach that takes advantage of the modular and multifunctional pRNA three-way junction platform in the SCI niche, while also exploiting the therapeutic potential of immune-compatible and feasible iNSC transplants. We show the combination of such treatments in a mouse model of contusion thoracic SCI leads to significant improvement of locomotor function, albeit not better than single pRNA-RNAi treatment, and results in synergistic histopathological effects, such as reduction of glial scar volume, diminished pro-inflammatory response, and promotion of neuronal survival. Our results provide evidence for a novel combinatorial approach for treating SCI.

Published
2020
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83. Abrogation of Gap Junctional Communication in ES Cells Results in a Disruption of Primitive Endoderm Formation in Embryoid Bodies

Author

Wörsdörfer, Philipp, primary, Bosen, Felicitas, additional, Gebhardt, Martina, additional, Russ, Nicole, additional, Zimmermann, Katrin, additional, Komla Kessie, David, additional, Sekaran, Thileepan, additional, Egert, Angela, additional, Ergün, Süleyman, additional, Schorle, Hubert, additional, Pfeifer, Alexander, additional, Edenhofer, Frank, additional, and Willecke, Klaus, additional

Published
2016
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91. BMP/SMAD Pathway Promotes Neurogenesis of Midbrain Dopaminergic Neurons In Vivo and in Human Induced Pluripotent and Neural Stem Cells.

Author

Jovanovic, Vukasin M., Salti, Ahmad, Tilleman, Hadas, Zega, Ksenija, Jukic, Marin M., Hongyan Zou, Friede, Roland H., Prakash, Nilima, Blaess, Sandra, Edenhofer, Frank, and Brodski, Claude

Subjects
EMBRYOLOGY, MESENCEPHALON, DOPAMINERGIC neurons, DEVELOPMENTAL neurobiology, NEURONAL differentiation, NEURAL stem cells, INDUCED pluripotent stem cells
Abstract

The embryonic formation of midbrain dopaminergic (mDA) neurons in vivo provides critical guidelines for the in vitro differentiation of mDA neurons from stem cells, which are currently being developed for Parkinson's disease cell replacement therapy. Bone morphogenetic protein (BMP)/SMAD inhibition is routinely used during early steps of stem cell differentiation protocols, including for the generation of mDA neurons. However, the function of the BMP/SMAD pathway for in vivo specification of mammalian mDA neurons is virtually unknown. Here, we report that BMP5/7-deficient mice (Bmp5-/-; Bmp7-/-) lackmDAneurons due to reduced neurogenesis in the mDA progenitor domain. As molecular mechanisms accounting for these alterations in Bmp5-/-; Bmp7-/- mutants, we have identified expression changes of the BMP/SMAD target genes MSX1/2 (msh homeobox 1/2) and SHH (sonic hedgehog). Conditionally inactivatingSMAD1in neural stem cells of mice in vivo (Smad1Nes) hampered the differentiation of progenitor cells intomDAneurons by preventing cell cycle exit, especially of TH+SOX6+ (tyrosine hydroxylase, SRY-box 6) and TH+GIRK2+ (potassium voltage-gated channel subfamily-J member-6) substantia nigra neurons. BMP5/7 robustly increased the in vitro differentiation of human induced pluripotent stem cells and induced neural stem cells to mDA neurons by up to threefold. In conclusion, we have identified BMP/SMAD signaling as a novel critical pathway orchestrating essential steps of mammalian mDA neurogenesis in vivo that balances progenitor proliferation and differentiation. Moreover, we demonstrate the potential of BMPs to improve the generation of stem-cell-derived mDA neurons in vitro, highlighting the importance of sequential BMP/SMAD inhibition and activation in this process. [ABSTRACT FROM AUTHOR]

Published
2018
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93. Abrogation of Gap Junctional Communication in ES Cells Results in a Disruption of Primitive Endoderm Formation in Embryoid Bodies.

Author

Wörsdörfer, Philipp, Bosen, Felicitas, Gebhardt, Martina, Russ, Nicole, Zimmermann, Katrin, Komla Kessie, David, Sekaran, Thileepan, Egert, Angela, Ergün, Süleyman, Schorle, Hubert, Pfeifer, Alexander, Edenhofer, Frank, and Willecke, Klaus

Abstract

Gap junctional intercellular communication (GJIC) has been suggested to be involved in early embryonic development but the actual functional role remained elusive. Connexin (Cx) 43 and Cx45 are co-expressed in embryonic stem (ES) cells, form gap junctions and are considered to exhibit adhesive function and/or to contribute to the establishment of defined communication compartments. Here, we describe the generation of Cx43/Cx45-double deficient mouse ES cells to achieve almost complete breakdown of GJIC. Cre-loxP induced deletion of both, Cx43 and Cx45, results in a block of differentiation in embryoid bodies (EBs) without affecting pluripotency marker expression and proliferation in ES cells. We demonstrate that GJIC-incompetent ES cells fail to form primitive endoderm in EB cultures, representing the inductive key step of further differentiation events. Lentiviral overexpression of either Cx43 or Cx45 in Cx43/45 mutants rescued the observed phenotype, confirming the specificity and indicating a partially redundant function of both connexins. Upon differentiation GJIC-incompetent ES cells exhibit a strikingly altered subcellular localization pattern of the transcription factor NFATc3. Control EBs exhibit significantly more activated NFATc3 in cellular nuclei than mutant EBs suggesting that Cx-mediated communication is needed for synchronized NFAT activation to induce orchestrated primitive endoderm formation. Moreover, pharmacological inhibition of NFATc3 activation by Cyclosporin A, a well-described inhibitor of calcineurin, phenocopies the loss of GJIC in control cells. S tem C ells 2017;35:859-871 [ABSTRACT FROM AUTHOR]

Published
2017
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94. Robust Generation of Cardiomyocytes from Human iPS Cells Requires Precise Modulation of BMP and WNT Signaling

Author

Kadari, Asifiqbal, primary, Mekala, SubbaRao, additional, Wagner, Nicole, additional, Malan, Daniela, additional, Köth, Jessica, additional, Doll, Katharina, additional, Stappert, Laura, additional, Eckert, Daniela, additional, Peitz, Michael, additional, Matthes, Jan, additional, Sasse, Philipp, additional, Herzig, Stefan, additional, Brüstle, Oliver, additional, Ergün, Süleyman, additional, and Edenhofer, Frank, additional

Published
2014
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97. Characterization of a novel cell penetrating peptide derived from human Oct4

Author

Harreither, Eva, primary, Rydberg, Hanna, additional, Amand, Helene, additional, Jadhav, Vaibhav, additional, Fliedl, Lukas, additional, Benda, Christina, additional, Esteban, Miguel, additional, Pei, Duanqing, additional, Borth, Nicole, additional, Grillari-Voglauer, Regina, additional, Hommerding, Oliver, additional, Edenhofer, Frank, additional, Nordén, Bengt, additional, and Grillari, Johannes, additional

Published
2014
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99. Novel reporter mouse reveals constitutive and inflammatory expression of IFN-beta in vivo.

Author

Lienenklaus, Stefan, Cornitescu, Marius, Zietara, Natalia, Łyszkiewicz, Marcin, Gekara, Nelson, Jabłónska, Jadwiga, Edenhofer, Frank, Rajewsky, Klaus, Bruder, Dunja, Hafner, Martin, Staeheli, Peter, Weiss, Siegfried, Lienenklaus, Stefan, Cornitescu, Marius, Zietara, Natalia, Łyszkiewicz, Marcin, Gekara, Nelson, Jabłónska, Jadwiga, Edenhofer, Frank, Rajewsky, Klaus, Bruder, Dunja, Hafner, Martin, Staeheli, Peter, and Weiss, Siegfried

Abstract

Type I IFN is a major player in innate and adaptive immune responses. Besides, it is involved in organogenesis and tumor development. Generally, IFN responses are amplified by an autocrine loop with IFN-beta as the priming cytokine. However, due to the lack of sensitive detection systems, where and how type I IFN is produced in vivo is still poorly understood. In this study, we describe a luciferase reporter mouse, which allows tracking of IFN-beta gene induction in vivo. Using this reporter mouse, we reveal strong tissue-specific induction of IFN-beta following infection with influenza or La Crosse virus. Importantly, this reporter mouse also allowed us to visualize that IFN-beta is expressed constitutively in several tissues. As suggested before, low amounts of constitutively produced IFN might maintain immune cells in an activated state ready for a timely response to pathogens. Interestingly, thymic epithelial cells were the major source of IFN-beta under noninflammatory conditions. This relatively high constitutive expression was controlled by the NF Aire and might influence induction of tolerance or T cell development.

Published
2009
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100. Nanog induces suppression of senescence through downregulation of p27KIP1 expression.

Author

Munst, Bernhard, Thier, Marc Christian, Winnemöller, Dirk, Helfen, Martina, Thummer, Rajkumar P., and Edenhofer, Frank

Subjects
PLURIPOTENT stem cells, CYTOLOGICAL research, CELL cycle, FIBROBLASTS, CELL proliferation, PHYSIOLOGY
Abstract

A comprehensive analysis of the molecular network of cellular factors establishing and maintaining pluripotency as well as self renewal of pluripotent stem cells is key for further progress in understanding basic stem cell biology. Nanog is necessary for the natural induction of pluripotency in early mammalian development but dispensable for both its maintenance and its artificial induction. To gain further insight into the molecular activity of Nanog, we analyzed the outcomes of Nanog gain-of-function in various cell models employing a recently developed biologically active recombinant cell-permeant protein, Nanog-TAT. We found that Nanog enhances the proliferation of both NIH 3T3 and primary fibroblast cells. Nanog transduction into primary fibroblasts results in suppression of senescence-associated β-galactosidase activity. Investigation of cell cycle factors revealed that transient activation of Nanog correlates with consistent downregulation of the cell cycle inhibitor p27KIP1 (also known as CDKN1B). By performing chromatin immunoprecipitation analysis, we confirmed bona fide Nanog-binding sites upstream of the p27KIP1 gene, establishing a direct link between physical occupancy and functional regulation. Our data demonstrates that Nanog enhances proliferation of fibroblasts through transcriptional regulation of cell cycle inhibitor p27 gene. [ABSTRACT FROM AUTHOR]

Published
2016
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