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3 results on '"SALVATORI, D."'

1. Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease

Author

Giacomelli, E, Meraviglia, V, Campostrini, G, Cochrane, A, Cao, X, van Helden, R, Krotenberg Garcia, A, Mircea, M, Kostidis, S, Davis, R, van Meer, B, Jost, C, Koster, A, Mei, H, Miguez, D, Mulder, A, Ledesma-Terron, M, Pompilio, G, Sala, L, Salvatori, D, Slieker, R, Sommariva, E, de Vries, A, Giera, M, Semrau, S, Tertoolen, L, Orlova, V, Bellin, M, Mummery, C, Giacomelli E., Meraviglia V., Campostrini G., Cochrane A., Cao X., van Helden R. W. J., Krotenberg Garcia A., Mircea M., Kostidis S., Davis R. P., van Meer B. J., Jost C. R., Koster A. J., Mei H., Miguez D. G., Mulder A. A., Ledesma-Terron M., Pompilio G., Sala L., Salvatori D. C. F., Slieker R. C., Sommariva E., de Vries A. A. F., Giera M., Semrau S., Tertoolen L. G. J., Orlova V. V., Bellin M., Mummery C. L., Giacomelli, E, Meraviglia, V, Campostrini, G, Cochrane, A, Cao, X, van Helden, R, Krotenberg Garcia, A, Mircea, M, Kostidis, S, Davis, R, van Meer, B, Jost, C, Koster, A, Mei, H, Miguez, D, Mulder, A, Ledesma-Terron, M, Pompilio, G, Sala, L, Salvatori, D, Slieker, R, Sommariva, E, de Vries, A, Giera, M, Semrau, S, Tertoolen, L, Orlova, V, Bellin, M, Mummery, C, Giacomelli E., Meraviglia V., Campostrini G., Cochrane A., Cao X., van Helden R. W. J., Krotenberg Garcia A., Mircea M., Kostidis S., Davis R. P., van Meer B. J., Jost C. R., Koster A. J., Mei H., Miguez D. G., Mulder A. A., Ledesma-Terron M., Pompilio G., Sala L., Salvatori D. C. F., Slieker R. C., Sommariva E., de Vries A. A. F., Giera M., Semrau S., Tertoolen L. G. J., Orlova V. V., Bellin M., and Mummery C. L.

Abstract

Cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) are functionally immature, but this is improved by incorporation into engineered tissues or forced contraction. Here, we showed that tri-cellular combinations of hiPSC-derived CMs, cardiac fibroblasts (CFs), and cardiac endothelial cells also enhance maturation in easily constructed, scaffold-free, three-dimensional microtissues (MTs). hiPSC-CMs in MTs with CFs showed improved sarcomeric structures with T-tubules, enhanced contractility, and mitochondrial respiration and were electrophysiologically more mature than MTs without CFs. Interactions mediating maturation included coupling between hiPSC-CMs and CFs through connexin 43 (CX43) gap junctions and increased intracellular cyclic AMP (cAMP). Scaled production of thousands of hiPSC-MTs was highly reproducible across lines and differentiated cell batches. MTs containing healthy-control hiPSC-CMs but hiPSC-CFs from patients with arrhythmogenic cardiomyopathy strikingly recapitulated features of the disease. Our MT model is thus a simple and versatile platform for modeling multicellular cardiac diseases that will facilitate industry and academic engagement in high-throughput molecular screening.

Published
2020

2. Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID.

Author

Garcia-Perez L, van Eggermond M, van Roon L, Vloemans SA, Cordes M, Schambach A, Rothe M, Berghuis D, Lagresle-Peyrou C, Cavazzana M, Zhang F, Thrasher AJ, Salvatori D, Meij P, Villa A, Van Dongen JJM, Zwaginga JJ, van der Burg M, Gaspar HB, Lankester A, Staal FJT, and Pike-Overzet K

Abstract

Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1 -/- mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34 + cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID., (© 2020 The Authors.)

Published
2020
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3. BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells.

Author

Gomes Fernandes M, Dries R, Roost MS, Semrau S, de Melo Bernardo A, Davis RP, Ramakrishnan R, Szuhai K, Maas E, Umans L, Abon Escalona V, Salvatori D, Deforce D, Van Criekinge W, Huylebroeck D, Mummery C, Zwijsen A, and de Sousa Lopes SM

Subjects
Animals, Bone Morphogenetic Proteins genetics, Cell Lineage genetics, Cell Self Renewal genetics, Cells, Cultured, DNA (Cytosine-5-)-Methyltransferases genetics, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dioxygenases, Gene Expression Profiling methods, Mice, Mice, Knockout, Mice, Transgenic, Microscopy, Confocal, Mouse Embryonic Stem Cells cytology, Pluripotent Stem Cells cytology, Pluripotent Stem Cells metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Smad Proteins, Receptor-Regulated genetics, Smad1 Protein genetics, Smad1 Protein metabolism, Smad5 Protein genetics, Smad5 Protein metabolism, Bone Morphogenetic Proteins metabolism, Cell Lineage physiology, Cell Self Renewal physiology, Mouse Embryonic Stem Cells metabolism, Signal Transduction physiology, Smad Proteins, Receptor-Regulated metabolism
Abstract

Naive mouse embryonic stem cells (mESCs) are in a metastable state and fluctuate between inner cell mass- and epiblast-like phenotypes. Here, we show transient activation of the BMP-SMAD signaling pathway in mESCs containing a BMP-SMAD responsive reporter transgene. Activation of the BMP-SMAD reporter transgene in naive mESCs correlated with lower levels of genomic DNA methylation, high expression of 5-methylcytosine hydroxylases Tet1/2 and low levels of DNA methyltransferases Dnmt3a/b. Moreover, naive mESCs, in which the BMP-SMAD reporter transgene was activated, showed higher resistance to differentiation. Using double Smad1;Smad5 knockout mESCs, we showed that BMP-SMAD signaling is dispensable for self-renewal in both naive and ground state. These mutant mESCs were still pluripotent, but they exhibited higher levels of DNA methylation than their wild-type counterparts and had a higher propensity to differentiate. We showed that BMP-SMAD signaling modulates lineage priming in mESCs, by transiently regulating the enzymatic machinery responsible for DNA methylation., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2016
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