Laboratory of William C. Claycomb
|Organized cardiac conduction system in an embryoid body|
The major interest of this laboratory is to develop mechanisms to repair or regenerate heart muscle tissue in the diseased heart. We are taking two major approaches. One is to understand the molecular machinery by which Nature restricts and irreversibly inhibits heart cell division during early development so that we can design procedures to reinitiate cell division to essentially regenerate muscle tissue. The other approach is to actually transplant heart muscle cells back into the diseased heart to repair or replace the injured muscle cells. Presently we are using mouse embryonic stem cells (ES Cells) to derive immortalized ventricular, atrial and conducting heart cell lines that retain a cardiac lineage-specific phenotype. This involves using a combinatorial selection process with multiple promoters and selectable markers. The idea is to create three different types of heart muscle cells that could be grown continuously in culture and be used as model systems to study the function and dysfunction of the ventricle, atria and conduction system of the heart. We have recently been successful in utilizing specific molecular markers to identify a cardiac conduction system utilizing differentiating ES cells in embryoid bodies. We are also utilizing these genetically engineered ES cells in a tissue-engineering project. These cells would be extremely useful as research reagents for basic cardiac muscle cell research such as growth regulation and signal transduction as well as for therapeutic applications such as transplantation of cells into a diseased heart to repair damaged heart muscle and as a cell replacement therapy to treat a wide variety of cardiomyopathies.
Hashem SI, Lam ML, Mihardja SS, White SM, Lee RJ, Claycomb WC.Shox2 Regulates the Pacemaker Gene Program in Embryoid Bodies. Stem Cells Dev. 2013 Jul 26. Open PDF of this article
Hashem SI, Claycomb WC.Genetic isolation of stem cell-derived pacemaker-nodal cardiac myocytes. Mol Cell Biochem. 2013 Jul 23. [Epub ahead of print] PMID: 23877224 Open PDF of this article
Fatima N, Schooley JF Jr, Claycomb WC, Flagg TP. Promoter DNA methylation regulates murine SUR1 (Abcc8) and SUR2 (Abcc9) expression in HL-1 cardiomyocytes. PLoS One. 2012;7(7):e41533. Epub 2012 Jul 23
Touchberry CD, Orange M, Weisleder N, Brotto M, Claycomb WC, Wacker MJ.Store-operated calcium entry is present in HL-1 cardiomyocytes and contributes to resting calcium.Biochem Biophys Res Commun.(2011) Nov 6. [Epub ahead of print]
Pieperhoff S, Rickelt S, Heid H, Claycomb W C, Kuhn C, Frey N, Franke WW.The plaque protein myozap identified as a novel major component of adhering junctions in endothelia of the blood and the lymph vascular systems.J Cell Mol Med. (2011) Oct 13.
Vinciguerra M, Santini MP, Claycomb WC, Ladurner AG and Rosenthal N.mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart. Aging Cell. (2011) In Press.
Lam ML, Hashem SI, Claycomb WC. Embryonic stem cell-derived cardiomyocytes harbor a subpopulation of niche-forming Sca-1+ progenitor cells. Molecular Cellular Biochemistry, 349:69-76 (2011)
Ma X, Jana SS, Conti MA, Kawamoto S, Claycomb WC, Adelstein RS.Ablation of Nonmuscle Myosin II-B and II-C Reveals a Role for Nonmuscle Myosin II in Cardiac Myocyte Karyokinesis. Moleular Biology of the Cell. (2011)21:3952-3962.
Dong C, Yang L, Zhang X, Gu H, Lam ML, Claycomb WC, Xia H, Wu G. Rab8 Interacts with Distinct Motifs in α2B- and β2-Adrenergic Receptors and Differentially Modulates Their Transport. J. Biol. Chem. 2010; 285: 20369-20380. Open PDF of this article
Vinciguerra M, Santini MP, Claycomb WC, Ladurner AG, Rosenthal N. Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity.
Aging (Albany NY). 2010; 2:43-62.
Ikeda K, Tojo K, Inada Y, Takada Y, Sakamoto M, Lam M, Claycomb WC, Tajima N. Regulation of urocortin I and its related peptide urocortin II by inflammatory and oxidative stresses in HL-1 cardiomyocytes. J Mol Endocrinol. 2009; 42:479-89.
Brunt KR, Tsuji MR, Lai JH, Kinobe RT, Durante W, Claycomb WC, Ward C, Melo LG .Heme Oxygenase-1 Inhibits Pro-Oxidant Induced Hypertrophy In HL-1 Cardiomyocytes.Exp Biol Med (Maywood). Feb 25.(2009)
Shimko VF, Claycomb WC, Effect of Mechanical Loading on Three-Dimensional Cultures of Embryonic Stem Cell-Derived Cardiomyocytes.Tissue Eng Part A. 2008; 14:49-58.
George CH, Rogers SA, Bertrand BM, Tunwell RE, Thomas NL, Steele DS, Cox EV, Pepper C, Hazeel CJ, Claycomb WC, Lai FA. Alternative splicing of ryanodine receptors modulates cardiomyocyte Ca2+ signaling and susceptibility to apoptosis. Circ Res. 2007; 100:874-83.
Hidalgo-Bastida LA, Barry JJ, Everitt NM, Rose FR, Buttery LD, Hall IP, Claycomb WC, Shakesheff KM. Cell adhesion and mechanical properties of a flexible scaffold for cardiac tissue engineering. Acta Biomater. 2007; 3:457-62.
Barnes K, Dobrzynski H, Foppolo S, Beal PR, Ismat F, Scullion ER, Sun L, Tellez J, Ritzel MW, Claycomb WC, Cass CE, Young JD, Billeter-Clark R, Boyett MR, Baldwin SA. Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH. Circ Res. 2006; 99:510-9.
Filipeanu CM, Zhou F, Lam ML, Kerut KE, Claycomb WC, Wu G. Enhancement of the recycling and activation of beta-adrenergic receptor by Rab4 GTPase in cardiac myocytes. J Biol Chem., Apr 21;281(16):11097-103 (2006)
Chandrasekar B, Mummidi SM, Claycomb WC, Mestril R, Nemer MD. Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase- phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes. J Biol Chem. Dec 1; (2004)
Filipeanu CM, Zhou F, Claycomb WC, Wu G. Regulation of the cell-surface expression and function of angiotensin II type 1 receptor by Rab1-mediated ER-to-Golgi transport in cardiac myocytes. J Biol Chem. Sep. 24;279(39):41077-84 (2004)
White SM, Constantin PE, Claycomb WC. Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am J Physiol Heart Circ Physiol. 2004; 286:H823-9.
Seymour EM, Wu SY, Kovach MA, Romano MA, Traynor JR, Claycomb WC, Bolling SF. HL-1 myocytes exhibit PKC and K(ATP) channel-dependent delta opioid preconditioning. J Surg Res.Oct;114(2):187-94 (2003)
White SM, Claycomb WC. Cardiac cell transplantation: protocols and applications. Methods Mol Biol., ;219:83-95. (2003) No abstract or PDF available
Lam ML, Bartoli M, Claycomb WC. The 21-day postnatal rat ventricular cardiac muscle cell in culture as an experimental model to study adult cardiomyocyte gene expression. Mol Cell Biochem., Jan.;229(1-2):51-62. (2002)
Neilan CL, Kenyon E, Kovach MA, Bowden K, Claycomb WC, Traynor JR, Bolling SF. An immortalized myocyte cell line, HL-1, expresses a functional delta –opioid receptor. J Mol Cell Cardiol., Dec;32(12):2187-93. (2000)
Lanson NA Jr, Egeland DB, Royals BA, Claycomb WC. The MRE11-NBS1-RAD50 pathway is perturbed in SV40 large T antigen-immortalized AT-1, AT-2 and HL-1 cardiomyocytes. Nucleic Acids Res., Aug. 1;28(15):2882-92.(2000)
Nguyen SV, Claycomb WC. Hypoxia regulates the expression of the adrenomedullin and HIF-1 genes in cultured HL-1 cardiomyocytes.Biochem Biophys Res Commun. Nov 19;265(2):382-6. (1999)
Cormier-Regard S, Nguyen SV, Claycomb WC. Adrenomedullin gene expression is developmentally regulated and induced byhypoxia in rat ventricular cardiac myocytes. J Biol Chem., Jul. 10;273(28):17787-92. (1998)
Watanabe E, Smith DM Jr, Delcarpio JB, Sun J, Smart FW, Van Meter CH Jr, Claycomb WC. Cardiomyocyte transplantation in a porcine myocardial infarction model. Cell Transplant, May-Jun.;7(3):239-46. (1998) View Abstract
Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ Jr. HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci U S A., 1998 Mar. 17;95(6):2979-84.
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