177 results found
Yue J, Xie M, Gou X, et al., 2014, Microtubules Regulate Focal Adhesion Dynamics through MAP4K4, DEVELOPMENTAL CELL, Vol: 31, Pages: 572-585, ISSN: 1534-5807
Qi B, Cong Q, Li P, et al., 2014, Ablation of Tak l in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice, Scientific Reports, Vol: 4, ISSN: 2045-2322
Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1−/− monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.
Foldes G, Matsa E, Kriston-Vizi J, et al., 2014, Aberrant alpha-adrenergic hypertrophic response in cardiomyocytes from human induced pluripotent cells, Stem Cell Reports, Vol: 3, Pages: 905-914, ISSN: 2213-6711
Cardiomyocytes from human embryonic stem cells (hESC-CMs) and induced pluripotent stem cells (hiPSC-CMs) represent new models for drug discovery. Although hypertrophy is a high-priority target, we found that hiPSC-CMs were systematically unresponsive to hypertrophic signals such as the α-adrenoceptor (αAR) agonist phenylephrine (PE) compared to hESC-CMs. We investigated signaling at multiple levels to understand the underlying mechanism of this differential responsiveness. The expression of the normal α1AR gene, ADRA1A, was reversibly silenced during differentiation, accompanied by ADRA1B upregulation in either cell type. ADRA1B signaling was intact in hESC-CMs, but not in hiPSC-CMs. We observed an increased tonic activity of inhibitory kinase pathways in hiPSC-CMs, and inhibition of antihypertrophic kinases revealed hypertrophic increases. There is tonic suppression of cell growth in hiPSC-CMs, but not hESC-CMs, limiting their use in investigation of hypertrophic signaling. These data raise questions regarding the hiPSC-CM as a valid model for certain aspects of cardiac disease.
Hasumi Y, Baba M, Hasumi H, et al., 2014, Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation, HUMAN MOLECULAR GENETICS, Vol: 23, Pages: 5706-5719, ISSN: 0964-6906
Weinreuter M, Kreusser MM, Beckendorf J, et al., 2014, CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury, EMBO Molecular Medicine, Vol: 6, Pages: 1231-1245, ISSN: 1757-4676
Lehmann LH, Rostosky JS, Buss SJ, et al., 2014, Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 111, Pages: 13499-13504, ISSN: 0027-8424
Kreusser MM, Lehmann LH, Keranov S, et al., 2014, Cardiac CaM Kinase II Genes delta and gamma Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy, Circulation, Vol: 130, Pages: 1262-1273, ISSN: 0009-7322
Chuang H-C, Sheu WH-H, Lin Y-T, et al., 2014, HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance, Nature Communications, Vol: 5, ISSN: 2041-1723
Proinflammatory cytokines play important roles in insulin resistance. Here we report thatmice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemicinflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradationand subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cellsaccumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells.Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulinresistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests thatleptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency inducesTRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adiposetissue and subsequent insulin resistance. These findings provide insight into the reciprocalregulation between the immune system and the metabolism.
Johannesson B, Sattler S, Semenova E, et al., 2014, Insulin-like growth factor-1 induces regulatory T cell-mediated suppression of allergic contact dermatitis in mice, DISEASE MODELS & MECHANISMS, Vol: 7, Pages: 977-985, ISSN: 1754-8403
Liu Y, Kaneda R, Leja TW, et al., 2014, Hhex and Cer1 Mediate the Sox17 Pathway for Cardiac Mesoderm Formation in Embryonic Stem Cells, STEM CELLS, Vol: 32, Pages: 1515-1526, ISSN: 1066-5099
Foeldes G, Mioulane M, Kodagoda T, et al., 2014, Immunosuppressive Agents Modulate Function, Growth, and Survival of Cardiomyocytes and Endothelial Cells Derived from Human Embryonic Stem Cells, STEM CELLS AND DEVELOPMENT, Vol: 23, Pages: 467-476, ISSN: 1547-3287
Stuckey DJ, McSweeney SJ, Thin MZ, et al., 2014, T-1 Mapping Detects Pharmacological Retardation of Diffuse Cardiac Fibrosis in Mouse Pressure-Overload Hypertrophy, CIRCULATION-CARDIOVASCULAR IMAGING, Vol: 7, Pages: 240-249, ISSN: 1941-9651
Fiedler LR, Maifoshie E, Schneider MD, 2014, Mouse Models of Heart Failure: Cell Signaling and Cell Survival, MOUSE MODELS OF THE NUCLEAR ENVELOPATHIES AND RELATED DISEASES, Vol: 109, Pages: 171-247, ISSN: 0070-2153
Arechederra M, Carmona R, Gonzalez-Nunez M, et al., 2013, Met signaling in cardiomyocytes is required for normal cardiac function in adult mice, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, Vol: 1832, Pages: 2204-2215, ISSN: 0925-4439
Oakley RH, Ren R, Cruz-Topete D, et al., 2013, Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 17035-17040, ISSN: 0027-8424
McSweeney SJ, Schneider MD, 2013, Virgin birth: engineered heart muscle from parthenogenetic stem cells, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 1010-1013, ISSN: 0021-9738
Lamothe B, Lai Y, Xie M, et al., 2013, TAK1 Is Essential for Osteoclast Differentiation and Is an Important Modulator of Cell Death by Apoptosis and Necroptosis, MOLECULAR AND CELLULAR BIOLOGY, Vol: 33, Pages: 582-595, ISSN: 0270-7306
Palacios JA, Schneider MD, 2013, Heart to heart: grafting cardiosphere-derived cells augments cardiac self-repair by both myocytes and stem cells, EMBO Molecular Medicine, Vol: 5, Pages: 177-179, ISSN: 1757-4676
Ibrahim M, Siedlecka U, Buyandelger B, et al., 2013, A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart, Hum Mol Genet, Vol: 22, Pages: 372-383, ISSN: 1460-2083
The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
Lamothe B, Lai Y, Hur L, et al., 2012, Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice, PLoS One, Vol: 7, Pages: 1-18, ISSN: 1932-6203
Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells’ increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1’s role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1’s role in leukemogenesis.
Mioulane M, Foldes G, Ali NN, et al., 2012, Development of high content imaging methods for cell death detection in human pluripotent stem cell-derived cardiomyocytes, Journal of Cardiovascular Translational Research, Vol: 5, Pages: 593-604, ISSN: 1937-5387
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) are being investigated as a new source of cardiac cells for drug safety assessment. We developed a novel scalable high content microscopy-based method for the detection of cell death in hPSC-CM that can serve for future predictive in vitro cardio-toxicological screens. Using rat neonatal ventricular cardiomyocytes (RVNC) or hPSC-CM, assays for nuclear remodelling, mitochondrial status, apoptosis and necrosis were designed using a combination of fluorescent dyes and antibodies on an automated microscopy platform. This allowed the observation of a chelerythrine-induced concentration-dependent apoptosis to necrosis switch and time-dependent progression of early apoptotic cells towards a necrotic-like phenotype. Susceptibility of hPSC-CM to chelerythrine-stimulated apoptosis varied with time after differentiation, but at most time points, hPSC-CM were more resistant than RVNC. This simple and scalable humanized high-content assay generates accurate cardiotoxicity profiles that can serve as a base for further assessment of cardioprotective strategies and drug safety.
Fox K, Schneider M, Shurlock B, 2012, Centre of Excellence: Imperial College of Science, Technology, and Medicine, London, England, CIRCULATION, Vol: 125, Pages: F139-F144, ISSN: 0009-7322
Schneider MD, 2012, Pioneer in Cardiovascular Research: Michael D. Schneider MD, FMedSci, FESC, FAHA, CIRCULATION, Vol: 125, Pages: F91-F95, ISSN: 0009-7322
Genet G, Guilbeau-Frugier C, Honton B, et al., 2012, Ephrin-B1 Is a Novel Specific Component of the Lateral Membrane of the Cardiomyocyte and Is Essential for the Stability of Cardiac Tissue Architecture Cohesion, CIRCULATION RESEARCH, Vol: 110, Pages: 688-U117, ISSN: 0009-7330
Shukla PC, Singh KK, Quan A, et al., 2011, BRCA1 is an essential regulator of heart function and survival following myocardial infarction, Nature Communications, Vol: 2, Pages: 1-11, ISSN: 2041-1723
The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure.
Schneider MD, 2011, EPO and Super-EPO: Erythropoietins Direct Neoangiogenesis by Cardiac Progenitor Cells, CELL STEM CELL, Vol: 9, Pages: 95-96, ISSN: 1934-5909
Schneider MD, 2011, A Cardiac Nonproliferation Treaty, SCIENCE, Vol: 332, Pages: 426-427, ISSN: 0036-8075
Mercola M, Ruiz-Lozano P, Schneider MD, 2011, Cardiac muscle regeneration: lessons from development, GENES & DEVELOPMENT, Vol: 25, Pages: 299-309, ISSN: 0890-9369
Noseda M, Peterkin T, Simoes FC, et al., 2011, Cardiopoietic Factors Extracellular Signals for Cardiac Lineage Commitment, CIRCULATION RESEARCH, Vol: 108, Pages: 129-152, ISSN: 0009-7330
Obeyesekere N, Ma F, Tesch G, et al., 2010, A POTENTIAL ROLE FOR TGF beta-ACTIVATED KINASE 1 (TAK1) EXPRESSION IN MONONUCLEAR PHAGOCYTES IN LPS-INDUCED ALBUMINURIA, NEPHROLOGY, Vol: 15, Pages: 94-94, ISSN: 1320-5358
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