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Arranz L.,Stem Cell Aging Group | Antonio H.-M.,Stem Cell Aging Group | Ligos J.M.,Cellomics Unit | De Molina A.,Animal Unit | And 2 more authors.
Cell Cycle | Year: 2012

Preservation of hematopoietic hierarchy requires a constant and reciprocal interplay between chromatin-specific epigenetic regulators and lineage-modifying transcription factors. The Polycomb member Bmi1 is a key factor in hematopoietic stem cell (HSC) maintenance, but its specific physiological role in subsequent hematopoietic lineagespecific commitments is unclear. Here, we generated conditional Bmi1 knockout (Bmi1-KO) mice. Selective ablation of Bmi1 in the hematopoietic system induced extensive upregulation of Ikaros, and concomitant Ikaros-dependent lymphoid-lineage transcriptional priming, which is marked by their loss of H2A ubiquitination and increased H3K4 trimethylation in Bmi1-KO long-term HSCs (LT-HSCs). Removal of Ikaros in Bmi1-null LT-HSCs significantly diminished the hematopoietic defects seen in conditional Bmi1-KO mice. These alterations resulted in recovering the Bmi1-KO exhausted quiescent stem-cell pool, whereas the block in Bmi1-KO lymphoid-progenitor differentiation was rescued, allowing the development of mature lymphoid cells. Together, our results indicate that Ikaros is a critical Bmi1 target in vivo that promotes premature lineage specification of HSCs. © 2012 Landes Bioscience.

Herrera-Merchan A.,Stem Cell Aging Group | Arranz L.,Stem Cell Aging Group | Ligos J.M.,Cellomic Unit | De Molina A.,Animal Unit | And 2 more authors.
Nature Communications | Year: 2012

Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self-renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gain-of-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and Ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies. © 2012 Macmillan Publishers Limited. All rights reserved.

Fernandez-Dominguez I.,Animal Unit | Echevarria-Uraga J.J.,Galdakao Usansolo Hospital | Gomez N.,Tecnalia | Luka Z.,Vanderbilt University | And 5 more authors.
Ultrasound in Medicine and Biology | Year: 2011

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of hepatic damage in developed countries. For this reason, mouse models of NAFLD have been developed to show progression of the disease because it perfectly resembles the human pathology. Here we show that diagnostic high-frequency ultrasound imaging (US) may be used as an effective method for monitoring the progression of liver disease, from steatosis to hepatocellular carcinoma in the methionine adenosyl transferase and glycine N-methyltransferase-deficient mice models. US reliably detected murine liver lesions associated with NAFLD in the two mice strains tested, with excellent agreement among US images, gross pathology and histological sections. Our results suggest US as a relevant approach for the study of NAFLD in mice, with interesting technical and therapeutic implications. © 2011 World Federation for Ultrasound in Medicine & Biology.

Carril M.,CIC Biomagune | Carril M.,Ikerbasque | Fernandez I.,Animal Unit | Rodriguez J.,Animal Unit | And 4 more authors.
Particle and Particle Systems Characterization | Year: 2014

In the pursuit of novel multimodal nanoprobes, the application of superparamagnetic gold-coated iron oxide nanoparticles (NPs) of 6 nm as contrast agents in phantoms for X-ray CT, US, and T2-weighted MRI is tested. It is hypothesized that the gold coating could increase the contrast of these NPs when irradiated with X-rays. The impact of the surrounding environment in the attenuation of gold coating is also evaluated by performing the measurements in air or in water to better mimic in vivo conditions. Additionally, it is proved that these NPs can enhance contrast in ultrasound scanning. Furthermore, their magnetite content is a known source of negative contrast in MRI. As expected, for the X-ray CT phantoms, there is a linear increase of contrast with concentration. Additionally, the attenuation of gold in water is lower than that of the same sample in air, and the rate of attenuation at different voltage varies differently depending on the surrounding media. Interestingly, it is possible to obtain brighter ultrasound images by using these NPs and their ultrasound signal increases with the concentration of the particles. Moreover, and as expected, T2-weighted MRI images become substantially darker as the concentration of iron increases. The obtained results and their comparative analysis show that these kinds of NPs can effectively be used as contrast agents in MRI, CT, and US. This could be an interesting starting point for future applications as multimodal contrast agents for targeted imaging. The application of gold-coated iron oxide nanoparticles as trimodal contrast agents for MRI, X-ray CT, and US is presented. Phantoms of different concentrations are measured in all three modalities at the same concentration for comparison purposes. Additionally, the effect of the energy of X-rays and the surrounding media of the samples is evaluated. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fernandez I.,Animal Unit | Pena A.,Animal Unit | Del Teso N.,Animal Unit | Perez V.,Animal Unit | Rodriguez-Cuesta J.,Animal Unit
Journal of the American Association for Laboratory Animal Science | Year: 2010

Collection of blood from the submandibular vein allows simple and rapid processing of many animals without anesthesia and facilitates rapid recovery with no signs of pain and discomfort in the mice. Here we compared the submandibular vein and retroorbital plexus blood collection methods, to determine the potential effect of the sampling technique on several clinical biochemistry parameters in C57BL/6J mice. We found statistically significant differences for 8 of the 9 biochemical parameters studied between the 2 blood sampling techniques. Compared with samples collected from the retroorbital plexus, blood obtained from the submadibular vein had higher levels of AST, ALT, protein, albumin, triglycerides, total cholesterol, and creatinine. Glucose values of retroorbital blood were higher than those from the submandibular vein. Urea levels were similar for both sampling techniques. Our results demonstrate that the technique used to obtain blood samples affects parameters commonly used to assess animal health. We recommend caution when comparing results of biochemical analysis of blood obtained from the submandibular vein in mice with reference values obtained by other blood sampling techniques. Copyright 2010 by the American Association for Laboratory Animal Science.

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