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  1. Article ; Online: Human iPSC modeling of heart disease for drug development.

    Hnatiuk, Anna P / Briganti, Francesca / Staudt, David W / Mercola, Mark

    Cell chemical biology

    2021  Volume 28, Issue 3, Page(s) 271–282

    Abstract: Human induced pluripotent stem cells (hiPSCs) have emerged as a promising platform for pharmacogenomics and drug development. In cardiology, they make it possible to produce unlimited numbers of patient-specific human cells that reproduce hallmark ... ...

    Abstract Human induced pluripotent stem cells (hiPSCs) have emerged as a promising platform for pharmacogenomics and drug development. In cardiology, they make it possible to produce unlimited numbers of patient-specific human cells that reproduce hallmark features of heart disease in the culture dish. Their potential applications include the discovery of mechanism-specific therapeutics, the evaluation of safety and efficacy in a human context before a drug candidate reaches patients, and the stratification of patients for clinical trials. Although this new technology has the potential to revolutionize drug discovery, translational hurdles have hindered its widespread adoption for pharmaceutical development. Here we discuss recent progress in overcoming these hurdles that should facilitate the use of hiPSCs to develop new medicines and individualize therapies for heart disease.
    MeSH term(s) Cardiovascular Agents/chemical synthesis ; Cardiovascular Agents/chemistry ; Cardiovascular Agents/pharmacology ; Drug Development ; Heart Diseases/drug therapy ; Heart Diseases/pathology ; Humans ; Induced Pluripotent Stem Cells/drug effects
    Chemical Substances Cardiovascular Agents
    Language English
    Publishing date 2021-03-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2021.02.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: High-resolution imaging of cardiomyocyte behavior reveals two distinct steps in ventricular trabeculation.

    Staudt, David W / Liu, Jiandong / Thorn, Kurt S / Stuurman, Nico / Liebling, Michael / Stainier, Didier Y R

    Development (Cambridge, England)

    2014  Volume 141, Issue 3, Page(s) 585–593

    Abstract: Over the course of development, the vertebrate heart undergoes a series of complex morphogenetic processes that transforms it from a simple myocardial epithelium to the complex 3D structure required for its function. One of these processes leads to the ... ...

    Abstract Over the course of development, the vertebrate heart undergoes a series of complex morphogenetic processes that transforms it from a simple myocardial epithelium to the complex 3D structure required for its function. One of these processes leads to the formation of trabeculae to optimize the internal structure of the ventricle for efficient conduction and contraction. Despite the important role of trabeculae in the development and physiology of the heart, little is known about their mechanism of formation. Using 3D time-lapse imaging of beating zebrafish hearts, we observed that the initiation of cardiac trabeculation can be divided into two processes. Before any myocardial cell bodies have entered the trabecular layer, cardiomyocytes extend protrusions that invade luminally along neighboring cell-cell junctions. These protrusions can interact within the trabecular layer to form new cell-cell contacts. Subsequently, cardiomyocytes constrict their abluminal surface, moving their cell bodies into the trabecular layer while elaborating more protrusions. We also examined the formation of these protrusions in trabeculation-deficient animals, including erbb2 mutants, tnnt2a morphants, which lack cardiac contractions and flow, and myh6 morphants, which lack atrial contraction and exhibit reduced flow. We found that, compared with cardiomyocytes in wild-type hearts, those in erbb2 mutants were less likely to form protrusions, those in tnnt2a morphants formed less stable protrusions, and those in myh6 morphants extended fewer protrusions per cell. Thus, through detailed 4D imaging of beating hearts, we have identified novel cellular behaviors underlying cardiac trabeculation.
    MeSH term(s) Animals ; Cell Surface Extensions/metabolism ; Heart Ventricles/anatomy & histology ; Heart Ventricles/cytology ; Heart Ventricles/growth & development ; Imaging, Three-Dimensional/methods ; Morphogenesis ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Zebrafish/growth & development
    Language English
    Publishing date 2014-01-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.098632
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: In Vivo Visualization of Cardiomyocyte Apicobasal Polarity Reveals Epithelial to Mesenchymal-like Transition during Cardiac Trabeculation.

    Jiménez-Amilburu, Vanesa / Rasouli, S Javad / Staudt, David W / Nakajima, Hiroyuki / Chiba, Ayano / Mochizuki, Naoki / Stainier, Didier Y R

    Cell reports

    2016  Volume 17, Issue 10, Page(s) 2687–2699

    Abstract: Despite great strides in understanding cardiac trabeculation, many mechanistic aspects remain unclear. To elucidate how cardiomyocyte shape changes are regulated during this process, we engineered transgenes to label their apical and basolateral ... ...

    Abstract Despite great strides in understanding cardiac trabeculation, many mechanistic aspects remain unclear. To elucidate how cardiomyocyte shape changes are regulated during this process, we engineered transgenes to label their apical and basolateral membranes. Using these tools, we observed that compact-layer cardiomyocytes are clearly polarized while delaminating cardiomyocytes have lost their polarity. The apical transgene also enabled the imaging of cardiomyocyte apical constriction in real time. Furthermore, we found that Neuregulin signaling and blood flow/cardiac contractility are required for cardiomyocyte apical constriction and depolarization. Notably, we observed the activation of Notch signaling in cardiomyocytes adjacent to those undergoing apical constriction, and we showed that this activation is positively regulated by Neuregulin signaling. Inhibition of Notch signaling did not increase the percentage of cardiomyocytes undergoing apical constriction or of trabecular cardiomyocytes. These studies provide information about cardiomyocyte polarization and enhance our understanding of the complex mechanisms underlying ventricular morphogenesis and maturation.
    Language English
    Publishing date 2016-12-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2016.11.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks.

    Celeste, Arkady / Fernandez-Capetillo, Oscar / Kruhlak, Michael J / Pilch, Duane R / Staudt, David W / Lee, Alicia / Bonner, Robert F / Bonner, William M / Nussenzweig, André

    Nature cell biology

    2003  Volume 5, Issue 7, Page(s) 675–679

    Abstract: Histone H2AX is rapidly phosphorylated in the chromatin micro-environment surrounding a DNA double-strand break (DSB). Although H2AX deficiency is not detrimental to life, H2AX is required for the accumulation of numerous essential proteins into ... ...

    Abstract Histone H2AX is rapidly phosphorylated in the chromatin micro-environment surrounding a DNA double-strand break (DSB). Although H2AX deficiency is not detrimental to life, H2AX is required for the accumulation of numerous essential proteins into irradiation induced foci (IRIF). However, the relationship between IRIF formation, H2AX phosphorylation (gamma-H2AX) and the detection of DNA damage is unclear. Here, we show that the migration of repair and signalling proteins to DSBs is not abrogated in H2AX(-/-) cells, or in H2AX-deficient cells that have been reconstituted with H2AX mutants that eliminate phosphorylation. Despite their initial recruitment to DSBs, numerous factors, including Nbs1, 53BP1 and Brca1, subsequently fail to form IRIF. We propose that gamma-H2AX does not constitute the primary signal required for the redistribution of repair complexes to damaged chromatin, but may function to concentrate proteins in the vicinity of DNA lesions. The differential requirements for factor recruitment to DSBs and sequestration into IRIF may explain why essential regulatory pathways controlling the ability of cells to respond to DNA damage are not abolished in the absence of H2AX.
    MeSH term(s) Animals ; Cell Line ; Cell Nucleus/genetics ; Chromatin/genetics ; DNA Damage/genetics ; DNA Damage/radiation effects ; DNA Repair/genetics ; DNA-Binding Proteins/genetics ; Eukaryotic Cells/metabolism ; Histones/deficiency ; Histones/genetics ; Humans ; Mice ; Nuclear Proteins/genetics ; Phosphorylation ; Signal Transduction/genetics
    Chemical Substances Chromatin ; DNA-Binding Proteins ; H2AX protein, human ; Histones ; Nuclear Proteins
    Language English
    Publishing date 2003-06-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/ncb1004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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