Zinc-deficiency acrodermatitis in a patient with chronic alcoholism and gastric bypass: a case report

Acquired adult-onset zinc deficiency is occasionally reported in patients with malnutrition states, such as alcoholism, or malabsorptive states, such as post-bariatric surgery. The defining symptoms of hypozincemia include a classic triad of necrolytic dermatitis, diffuse alopecia, and diarrhea. We report a case of zinc deficiency in a 39-year-old man with history of gastric bypass surgery and alcoholism. For this patient, severe hypozincemia confirmed acrodermatitis, and zinc supplementation was met with gradual improvement

Increased transport of acetylâ CoA into the endoplasmic reticulum causes a progeriaâ like phenotype

The membrane transporter ATâ 1/SLC33A1 translocates cytosolic acetylâ CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in ATâ 1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of ATâ 1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the ATâ 1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9aâ Fam134bâ LC3β and Atg9aâ Sec62â LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of ATâ 1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetylâ CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetylâ CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosolâ toâ ER flux of acetylâ CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetylâ CoAâ dependent homeostatic mechanisms linked to metabolism and inflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146343/1/acel12820-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146343/2/acel12820.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146343/3/acel12820_am.pd

In vitro development of bioimplants made up of elastomeric scaffolds with peptide gel filling seeded with human subcutaneous adipose tissue-derived progenitor cells

[EN] Myocardial tissue lacks the ability to regenerate itself significantly following a myocardial infarction. Thus, new strategies that could compensate this lack are of high interest. Cardiac tissue engineering (CTE) strategies are a relatively new approach that aims to compensate the tissue loss using combination of biomaterials, cells and bioactive molecules. The goal of the present study was to evaluate cell survival and growth, seeding capacity and cellular phenotype maintenance of subcutaneous adipose tissue-derived progenitor cells in a new synthetic biomaterial scaffold platform. Specifically, here we tested the effect of the RAD16-I peptide gel in microporous poly(ethyl acrylate) polymers using two-dimensional PEA films as controls. Results showed optimal cell adhesion efficiency and growth in the polymers coated with the self-assembling peptide RAD16-I. Importantly, subATDPCs seeded into microporous PEA scaffolds coated with RAD16-I maintained its phenotype and were able to migrate outwards the bioactive patch, hopefully toward the infarcted area once implanted. These data suggest that this bioimplant (scaffold/RAD16-I/cells) can be suitable for further in vivo implantation with the aim to improve the function of affected tissue after myocardial infarction. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 3419-3430, 2015.Contract grant sponsor: European Union Seventh Framework Programme; contract grant number: 229239Castells-Sala, C.; Martínez Ramos, C.; Vallés Lluch, A.; Monleón Pradas, M.; Semino, C. (2015). In vitro development of bioimplants made up of elastomeric scaffolds with peptide gel filling seeded with human subcutaneous adipose tissue-derived progenitor cells. Journal of Biomedical Materials Research Part A. 103(11):3419-3430. https://doi.org/10.1002/jbm.a.35482S3419343010311Persidis, A. (1999). Tissue engineering. Nature Biotechnology, 17(5), 508-510. doi:10.1038/8700Venugopal, J. R., Prabhakaran, M. P., Mukherjee, S., Ravichandran, R., Dan, K., & Ramakrishna, S. (2011). Biomaterial strategies for alleviation of myocardial infarction. Journal of The Royal Society Interface, 9(66), 1-19. doi:10.1098/rsif.2011.0301Castells-Sala, C., & Semino, C. E. (2012). Biomaterials for stem cell culture and seeding for the generation and delivery of cardiac myocytes. Current Opinion in Organ Transplantation, 17(6), 681-687. doi:10.1097/mot.0b013e32835a34a6Nunes, S. S., Song, H., Chiang, C. K., & Radisic, M. (2011). Stem Cell-Based Cardiac Tissue Engineering. Journal of Cardiovascular Translational Research, 4(5), 592-602. doi:10.1007/s12265-011-9307-xFernandes, S., Kuklok, S., McGonigle, J., Reinecke, H., & Murry, C. E. (2012). Synthetic Matrices to Serve as Niches for Muscle Cell Transplantation. Cells Tissues Organs, 195(1-2), 48-59. doi:10.1159/000331414Murry, C. E., Field, L. J., & Menasché, P. (2005). Cell-Based Cardiac Repair. Circulation, 112(20), 3174-3183. doi:10.1161/circulationaha.105.546218Wang, F., & Guan, J. (2010). Cellular cardiomyoplasty and cardiac tissue engineering for myocardial therapy☆. Advanced Drug Delivery Reviews, 62(7-8), 784-797. doi:10.1016/j.addr.2010.03.001Patel, A. N., & Genovese, J. A. (2007). Stem cell therapy for the treatment of heart failure. Current Opinion in Cardiology, 22(5), 464-470. doi:10.1097/hco.0b013e3282c3cb2aPendyala, L., Goodchild, T., Gadesam, R., Chen, J., Robinson, K., Chronos, N., & Hou, D. (2008). Cellular Cardiomyoplasty and Cardiac Regeneration. Current Cardiology Reviews, 4(2), 72-80. doi:10.2174/157340308784245748Li, Z., Guo, X., & Guan, J. (2012). A Thermosensitive Hydrogel Capable of Releasing bFGF for Enhanced Differentiation of Mesenchymal Stem Cell into Cardiomyocyte-like Cells under Ischemic Conditions. Biomacromolecules, 13(6), 1956-1964. doi:10.1021/bm300574jHuang, C.-C., Wei, H.-J., Yeh, Y.-C., Wang, J.-J., Lin, W.-W., Lee, T.-Y., … Sung, H.-W. (2012). Injectable PLGA porous beads cellularized by hAFSCs for cellular cardiomyoplasty. Biomaterials, 33(16), 4069-4077. doi:10.1016/j.biomaterials.2012.02.024Liu, Z., Wang, H., Wang, Y., Lin, Q., Yao, A., Cao, F., … Wang, C. (2012). The influence of chitosan hydrogel on stem cell engraftment, survival and homing in the ischemic myocardial microenvironment. Biomaterials, 33(11), 3093-3106. doi:10.1016/j.biomaterials.2011.12.044Kadner, K., Dobner, S., Franz, T., Bezuidenhout, D., Sirry, M. S., Zilla, P., & Davies, N. H. (2012). The beneficial effects of deferred delivery on the efficiency of hydrogel therapy post myocardial infarction. Biomaterials, 33(7), 2060-2066. doi:10.1016/j.biomaterials.2011.11.031Naderi, H., Matin, M. M., & Bahrami, A. R. (2011). Review paper: Critical Issues in Tissue Engineering: Biomaterials, Cell Sources, Angiogenesis, and Drug Delivery Systems. Journal of Biomaterials Applications, 26(4), 383-417. doi:10.1177/0885328211408946Ptaszek, L. M., Mansour, M., Ruskin, J. N., & Chien, K. R. (2012). Towards regenerative therapy for cardiac disease. The Lancet, 379(9819), 933-942. doi:10.1016/s0140-6736(12)60075-0Song, H., Yoon, C., Kattman, S. J., Dengler, J., Massé, S., Thavaratnam, T., … Zandstra, P. W. (2009). Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue. Proceedings of the National Academy of Sciences, 107(8), 3329-3334. doi:10.1073/pnas.0905729106Liu, J., Zhang, Z., Liu, Y., Guo, C., Gong, Y., Yang, S., … He, Z. (2012). Generation, Characterization, and Potential Therapeutic Applications of Cardiomyocytes from Various Stem Cells. Stem Cells and Development, 21(12), 2095-2110. doi:10.1089/scd.2012.0031Abdelli, L. S., Merino, H., Rocher, C. M., & Singla, D. K. (2012). Cell therapy in the heart. Canadian Journal of Physiology and Pharmacology, 90(3), 307-315. doi:10.1139/y11-130Hoover-Plow, J., & Gong, Y. (2012). Challenges for heart disease stem cell therapy. Vascular Health and Risk Management, 99. doi:10.2147/vhrm.s25665Chachques, J. C., Trainini, J. C., Lago, N., Cortes-Morichetti, M., Schussler, O., & Carpentier, A. (2008). Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Trial): Clinical Feasibility Study. The Annals of Thoracic Surgery, 85(3), 901-908. doi:10.1016/j.athoracsur.2007.10.052Karam, J.-P., Muscari, C., & Montero-Menei, C. N. (2012). Combining adult stem cells and polymeric devices for tissue engineering in infarcted myocardium. Biomaterials, 33(23), 5683-5695. doi:10.1016/j.biomaterials.2012.04.028Clifford, D. M., Fisher, S. A., Brunskill, S. J., Doree, C., Mathur, A., Clarke, M. J., … Martin-Rendon, E. (2012). Long-Term Effects of Autologous Bone Marrow Stem Cell Treatment in Acute Myocardial Infarction: Factors That May Influence Outcomes. PLoS ONE, 7(5), e37373. doi:10.1371/journal.pone.0037373Lee, R. H., Kim, B., Choi, I., Kim, H., Choi, H. S., Suh, K., … Jung, J. S. (2004). Characterization and Expression Analysis of Mesenchymal Stem Cells from Human Bone Marrow and Adipose Tissue. Cellular Physiology and Biochemistry, 14(4-6), 311-324. doi:10.1159/000080341Qayyum, A. A., Haack-Sørensen, M., Mathiasen, A. B., Jørgensen, E., Ekblond, A., & Kastrup, J. (2012). Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial): study design. Regenerative Medicine, 7(3), 421-428. doi:10.2217/rme.12.17Bai, X., Ma, J., Pan, Z., Song, Y.-H., Freyberg, S., Yan, Y., … Alt, E. (2007). Electrophysiological properties of human adipose tissue-derived stem cells. American Journal of Physiology-Cell Physiology, 293(5), C1539-C1550. doi:10.1152/ajpcell.00089.2007Rigol, M., Solanes, N., Farré, J., Roura, S., Roqué, M., Berruezo, A., … Heras, M. (2010). Effects of Adipose Tissue-Derived Stem Cell Therapy After Myocardial Infarction: Impact of the Route of Administration. Journal of Cardiac Failure, 16(4), 357-366. doi:10.1016/j.cardfail.2009.12.006Planat-Bénard, V., Menard, C., André, M., Puceat, M., Perez, A., Garcia-Verdugo, J.-M., … Casteilla, L. (2004). Spontaneous Cardiomyocyte Differentiation From Adipose Tissue Stroma Cells. Circulation Research, 94(2), 223-229. doi:10.1161/01.res.0000109792.43271.47Weber, B., Zeisberger, S. M., & Hoerstrup, S. P. (2011). Prenatally harvested cells for cardiovascular tissue engineering: Fabrication of autologous implants prior to birth. Placenta, 32, S316-S319. doi:10.1016/j.placenta.2011.04.001Cortes-Morichetti, M., Frati, G., Schussler, O., Van Huyen, J.-P. D., Lauret, E., Genovese, J. A., … Chachques, J. C. (2007). Association Between a Cell-Seeded Collagen Matrix and Cellular Cardiomyoplasty for Myocardial Support and Regeneration. Tissue Engineering, 13(11), 2681-2687. doi:10.1089/ten.2006.0447Chi, N.-H., Yang, M.-C., Chung, T.-W., Chen, J.-Y., Chou, N.-K., & Wang, S.-S. (2012). Cardiac repair achieved by bone marrow mesenchymal stem cells/silk fibroin/hyaluronic acid patches in a rat of myocardial infarction model. Biomaterials, 33(22), 5541-5551. doi:10.1016/j.biomaterials.2012.04.030Wang, T., Jiang, X.-J., Tang, Q.-Z., Li, X.-Y., Lin, T., Wu, D.-Q., … Okello, E. (2009). Bone marrow stem cells implantation with α-cyclodextrin/MPEG–PCL–MPEG hydrogel improves cardiac function after myocardial infarction. Acta Biomaterialia, 5(8), 2939-2944. doi:10.1016/j.actbio.2009.04.040Wu, J., Zeng, F., Huang, X.-P., Chung, J. C.-Y., Konecny, F., Weisel, R. D., & Li, R.-K. (2011). Infarct stabilization and cardiac repair with a VEGF-conjugated, injectable hydrogel. Biomaterials, 32(2), 579-586. doi:10.1016/j.biomaterials.2010.08.098Vunjak-Novakovic, G., Lui, K. O., Tandon, N., & Chien, K. R. (2011). Bioengineering Heart Muscle: A Paradigm for Regenerative Medicine. Annual Review of Biomedical Engineering, 13(1), 245-267. doi:10.1146/annurev-bioeng-071910-124701Dobner, S., Bezuidenhout, D., Govender, P., Zilla, P., & Davies, N. (2009). A Synthetic Non-degradable Polyethylene Glycol Hydrogel Retards Adverse Post-infarct Left Ventricular Remodeling. Journal of Cardiac Failure, 15(7), 629-636. doi:10.1016/j.cardfail.2009.03.003Blan, N. R., & Birla, R. K. (2008). Design and fabrication of heart muscle using scaffold-based tissue engineering. Journal of Biomedical Materials Research Part A, 86A(1), 195-208. doi:10.1002/jbm.a.31642Zhao, X., & Zhang, S. (s. f.). Self-Assembling Nanopeptides Become a New Type of Biomaterial. Advances in Polymer Science, 145-170. doi:10.1007/12_088Vallés-Lluch, A., Arnal-Pastor, M., Martínez-Ramos, C., Vilariño-Feltrer, G., Vikingsson, L., Castells-Sala, C., … Monleón Pradas, M. (2013). Combining self-assembling peptide gels with three-dimensional elastomer scaffolds. Acta Biomaterialia, 9(12), 9451-9460. doi:10.1016/j.actbio.2013.07.038Arnal-Pastor, M., Vallés-Lluch, A., Keicher, M., & Pradas, M. M. (2011). Coating typologies and constrained swelling of hyaluronic acid gels within scaffold pores. Journal of Colloid and Interface Science, 361(1), 361-369. doi:10.1016/j.jcis.2011.05.013Pérez Olmedilla, M., Garcia-Giralt, N., Pradas, M. M., Ruiz, P. B., Gómez Ribelles, J. L., Palou, E. C., & García, J. C. M. (2006). Response of human chondrocytes to a non-uniform distribution of hydrophilic domains on poly (ethyl acrylate-co-hydroxyethyl methacrylate) copolymers. Biomaterials, 27(7), 1003-1012. doi:10.1016/j.biomaterials.2005.07.030Soria, J. M., Martínez Ramos, C., Salmerón Sánchez, M., Benavent, V., Campillo Fernández, A., Gómez Ribelles, J. L., … Barcia, J. A. (2006). Survival and differentiation of embryonic neural explants on different biomaterials. Journal of Biomedical Materials Research Part A, 79A(3), 495-502. doi:10.1002/jbm.a.30803Campillo-Fernandez, A. J., Pastor, S., Abad-Collado, M., Bataille, L., Gomez-Ribelles, J. L., Meseguer-Dueñas, J. M., … Ruiz-Moreno, J. M. (2007). Future Design of a New Keratoprosthesis. Physical and Biological Analysis of Polymeric Substrates for Epithelial Cell Growth. Biomacromolecules, 8(8), 2429-2436. doi:10.1021/bm0703012Martínez-Ramos, C., Vallés-Lluch, A., Verdugo, J. M. G., Ribelles, J. L. G., Barcia Albacar, J. A., Orts, A. B., … Pradas, M. M. (2012). Channeled scaffolds implanted in adult rat brain. Journal of Biomedical Materials Research Part A, 100A(12), 3276-3286. doi:10.1002/jbm.a.34273Hernández, J. C. R., Salmerón Sánchez, M., Soria, J. M., Gómez Ribelles, J. L., & Monleón Pradas, M. (2007). Substrate Chemistry-Dependent Conformations of Single Laminin Molecules on Polymer Surfaces are Revealed by the Phase Signal of Atomic Force Microscopy. Biophysical Journal, 93(1), 202-207. doi:10.1529/biophysj.106.102491Kisiday, J., Jin, M., Kurz, B., Hung, H., Semino, C., Zhang, S., & Grodzinsky, A. J. (2002). Self-assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division: Implications for cartilage tissue repair. Proceedings of the National Academy of Sciences, 99(15), 9996-10001. doi:10.1073/pnas.142309999Semino, C. E., Merok, J. R., Crane, G. G., Panagiotakos, G., & Zhang, S. (2003). Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds. Differentiation, 71(4-5), 262-270. doi:10.1046/j.1432-0436.2003.7104503.xNarmoneva, D. A., Vukmirovic, R., Davis, M. E., Kamm, R. D., & Lee, R. T. (2004). Endothelial Cells Promote Cardiac Myocyte Survival and Spatial Reorganization. Circulation, 110(8), 962-968. doi:10.1161/01.cir.0000140667.37070.07Genové, E., Shen, C., Zhang, S., & Semino, C. E. (2005). The effect of functionalized self-assembling peptide scaffolds on human aortic endothelial cell function. Biomaterials, 26(16), 3341-3351. doi:10.1016/j.biomaterials.2004.08.012Ellis-Behnke, R. G., Liang, Y.-X., You, S.-W., Tay, D. K. C., Zhang, S., So, K.-F., & Schneider, G. E. (2006). Nano neuro knitting: Peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision. Proceedings of the National Academy of Sciences, 103(13), 5054-5059. doi:10.1073/pnas.0600559103Garreta, E., Genové, E., Borrós,, S., & Semino, C. E. (2006). Osteogenic Differentiation of Mouse Embryonic Stem Cells and Mouse Embryonic Fibroblasts in a Three-Dimensional Self-Assembling Peptide Scaffold. Tissue Engineering, 12(8), 2215-2227. doi:10.1089/ten.2006.12.2215Martínez-Ramos, C., Rodríguez-Pérez, E., Garnes, M. P., Chachques, J. C., Moratal, D., Vallés-Lluch, A., & Monleón Pradas, M. (2014). Design and Assembly Procedures for Large-Sized Biohybrid Scaffolds as Patches for Myocardial Infarct. Tissue Engineering Part C: Methods, 20(10), 817-827. doi:10.1089/ten.tec.2013.0489Diego, R. B., Olmedilla, M. P., Aroca, A. S., Ribelles, J. L. G., Pradas, M. M., Ferrer, G. G., & Sánchez, M. S. (2005). Acrylic scaffolds with interconnected spherical pores and controlled hydrophilicity for tissue engineering. Journal of Materials Science: Materials in Medicine, 16(8), 693-698. doi:10.1007/s10856-005-2604-7Diego, R. B., Estellés, J. M., Sanz, J. A., García-Aznar, J. M., & Sánchez, M. S. (2007). Polymer scaffolds with interconnected spherical pores and controlled architecture for tissue engineering: Fabrication, mechanical properties, and finite element modeling. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 81B(2), 448-455. doi:10.1002/jbm.b.30683Bayes-Genis, A., Soler-Botija, C., Farré, J., Sepúlveda, P., Raya, A., Roura, S., … Belmonte, J. C. I. (2010). Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents. Journal of Molecular and Cellular Cardiology, 49(5), 771-780. doi:10.1016/j.yjmcc.2010.08.010MARTINEZESTRADA, O., MUNOZSANTOS, Y., JULVE, J., REINA, M., & VILARO, S. (2005). Human adipose tissue as a source of Flk-1 cells: new method of differentiation and expansion. Cardiovascular Research, 65(2), 328-333. doi:10.1016/j.cardiores.2004.11.015Cyganek, L. (2013). Cardiac Progenitor Cells and their Therapeutic Application for Cardiac Repair. Journal of Clinical & Experimental Cardiology, 01(S11). doi:10.4172/2155-9880.s11-008Wang, C., Cao, D., Wang, Q., & Wang, D.-Z. (2011). Synergistic Activation of Cardiac Genes by Myocardin and Tbx5. PLoS ONE, 6(8), e24242. doi:10.1371/journal.pone.0024242Wilson-Rawls, J., Molkentin, J. D., Black, B. L., & Olson, E. N. (1999). Activated Notch Inhibits Myogenic Activity of the MADS-Box Transcription Factor Myocyte Enhancer Factor 2C. Molecular and Cellular Biology, 19(4), 2853-2862. doi:10.1128/mcb.19.4.2853Lockhart, M. M., Wirrig, E. E., Phelps, A. L., Ghatnekar, A. V., Barth, J. L., Norris, R. A., & Wessels, A. (2013). Mef2c Regulates Transcription of the Extracellular Matrix Protein Cartilage Link Protein 1 in the Developing Murine Heart. PLoS ONE, 8(2), e57073. doi:10.1371/journal.pone.0057073Jiang, W., Ma, A., Wang, T., Han, K., Liu, Y., Zhang, Y., … Zheng, X. (2006). Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study. Pflügers Archiv - European Journal of Physiology, 453(1), 43-52. doi:10.1007/s00424-006-0117-yPrabhakaran, M. P., Venugopal, J., Kai, D., & Ramakrishna, S. (2011). Biomimetic material strategies for cardiac tissue engineering. Materials Science and Engineering: C, 31(3), 503-513. doi:10.1016/j.msec.2010.12.017Xu, B., Li, Y., Fang, X., Thouas, G. A., Cook, W. D., Newgreen, D. F., & Chen, Q. (2013). Mechanically tissue-like elastomeric polymers and their potential as a vehicle to deliver functional cardiomyocytes. Journal of the Mechanical Behavior of Biomedical Materials, 28, 354-365. doi:10.1016/j.jmbbm.2013.06.005Zhou, J., Shu, Y., Lü, S.-H., Li, J.-J., Sun, H.-Y., Tang, R.-Y., … Wang, C.-Y. (2013). The Spatiotemporal Development of Intercalated Disk in Three-Dimensional Engineered Heart Tissues Based on Collagen/Matrigel Matrix. PLoS ONE, 8(11), e81420. doi:10.1371/journal.pone.0081420Zhang, S., Gelain, F., & Zhao, X. (2005). Designer self-assembling peptide nanofiber scaffolds for 3D tissue cell cultures. Seminars in Cancer Biology, 15(5), 413-420. doi:10.1016/j.semcancer.2005.05.007Santos, E., Hernández, R. M., Pedraz, J. L., & Orive, G. (2012). Novel advances in the design of three-dimensional bio-scaffolds to control cell fate: translation from 2D to 3D. Trends in Biotechnology, 30(6), 331-341. doi:10.1016/j.tibtech.2012.03.005Dégano, I. R., Quintana, L., Vilalta, M., Horna, D., Rubio, N., Borrós, S., … Blanco, J. (2009). The effect of self-assembling peptide nanofiber scaffolds on mouse embryonic fibroblast implantation and proliferation. Biomaterials, 30(6), 1156-1165. doi:10.1016/j.biomaterials.2008.11.021Kanno, S., & Saffitz, J. E. (2001). The role of myocardial gap junctions in electrical conduction and arrhythmogenesis. Cardiovascular Pathology, 10(4), 169-177. doi:10.1016/s1054-8807(01)00078-3Center CHG 1996Messner, B., Baum, H., Fischer, P., Quasthoff, S., & Neumeier, D. (2000). Expression of Messenger RNA of the Cardiac Isoforms of Troponin T and I in Myopathic Skeletal Muscle. American Journal of Clinical Pathology, 114(4), 544-549. doi:10.1309/8kcl-uqrf-6eel-36xkGnecchi, M., Danieli, P., & Cervio, E. (2012). Mesenchymal stem cell therapy for heart disease. Vascular Pharmacology, 57(1), 48-55. doi:10.1016/j.vph.2012.04.00

Terminal Differentiation, Advanced Organotypic Maturation, and Modeling of Hypertrophic Growth in Engineered Heart Tissue

Rationale: Cardiac tissue engineering should provide "realistic" in vitro heart muscle models and surrogate tissue for myocardial repair. For either application, engineered myocardium should display features of native myocardium, including terminal differentiation, organotypic maturation, and hypertrophic growth. Objective: To test the hypothesis that 3D-engineered heart tissue (EHT) culture supports (1) terminal differentiation as well as (2) organotypic assembly and maturation of immature cardiomyocytes, and (3) constitutes a methodological platform to investigate mechanisms underlying hypertrophic growth. Methods and Results: We generated EHTs from neonatal rat cardiomyocytes and compared morphological and molecular properties of EHT and native myocardium from fetal, neonatal, and adult rats. We made the following key observations: cardiomyocytes in EHT (1) gained a high level of binucleation in the absence of notable cytokinesis, (2) regained a rod-shape and anisotropic sarcomere organization, (3) demonstrated a fetal-to-adult gene expression pattern, and (4) responded to distinct hypertrophic stimuli with concentric or eccentric hypertrophy and reexpression of fetal genes. The process of terminal differentiation and maturation (culture days 7-12) was preceded by a tissue consolidation phase (culture days 0-7) with substantial cardiomyocyte apoptosis and dynamic extracellular matrix restructuring. Conclusions: This study documents the propensity of immature cardiomyocytes to terminally differentiate and mature in EHT in a remarkably organotypic manner. It moreover provides the rationale for the utility of the EHT technology as a methodological bridge between 2D cell culture and animal models. (Circ Res. 2011;109:1105-1114.

Cockayne syndrome:Clinical features, model systems and pathways

Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1, 2 and 3) and complementation groups (CSA and CSB), and overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been considered to be due to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility of molecular interventions in CS, and by extrapolation, possibly in aging

CSB: An Emerging Actionable Target for Cancer Therapy

The DNA repair protein Cockayne syndrome group B (CSB) is frequently found overexpressed in cancer cells. High CSB levels favor tumor cell proliferation whilst inhibiting apoptosis. Conversely, the suppression of CSB has significant anticancer effects. In this manuscript we describe CSB downregulation as a potential new therapeutic approach in cancer

Age-associated expression of p21and p53 during human wound healing.

In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated β-galactosidase (SA-β-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects