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4. Myocardial overexpression of ANKRD1 causes sinus venosus defects and progressive diastolic dysfunction

Author

Piroddi, N, Pesce, P, Scellini, B, Manzini, S, Ganzetti, G, Badi, I, Menegollo, M, Cora, V, Tiso, S, Cinquetti, R, Monti, L, Chiesa, G, Bleyl, S, Busnelli, M, Dellera, F, Bruno, D, Caicci, F, Grimaldi, A, Taramelli, R, Manni, L, Sacerdoti, D, Tesi, C, Poggesi, C, Ausoni, S, Acquati, F, Campione, M, Piroddi N., Pesce P., Scellini B., Manzini S., Ganzetti G. S., Badi I., Menegollo M., Cora V., Tiso S., Cinquetti R., Monti L., Chiesa G., Bleyl S. B., Busnelli M., Dellera F., Bruno D., Caicci F., Grimaldi A., Taramelli R., Manni L., Sacerdoti D., Tesi C., Poggesi C., Ausoni S., Acquati F., Campione M., Piroddi, N, Pesce, P, Scellini, B, Manzini, S, Ganzetti, G, Badi, I, Menegollo, M, Cora, V, Tiso, S, Cinquetti, R, Monti, L, Chiesa, G, Bleyl, S, Busnelli, M, Dellera, F, Bruno, D, Caicci, F, Grimaldi, A, Taramelli, R, Manni, L, Sacerdoti, D, Tesi, C, Poggesi, C, Ausoni, S, Acquati, F, Campione, M, Piroddi N., Pesce P., Scellini B., Manzini S., Ganzetti G. S., Badi I., Menegollo M., Cora V., Tiso S., Cinquetti R., Monti L., Chiesa G., Bleyl S. B., Busnelli M., Dellera F., Bruno D., Caicci F., Grimaldi A., Taramelli R., Manni L., Sacerdoti D., Tesi C., Poggesi C., Ausoni S., Acquati F., and Campione M.

Abstract

Aims Increased Ankyrin Repeat Domain 1 (ANKRD1) levels linked to gain of function mutations have been associated to total anomalous pulmonary venous return and adult cardiomyopathy occurrence in humans. The link between increased ANKRD1 level and cardiac structural and functional disease is not understood. To get insight into this problem, we have generated a gain of function ANKRD1 mouse model by overexpressing ANKRD1 in the myocardium.Methods and results Ankrd1 is expressed non-homogeneously in the embryonic myocardium, with a dynamic nucleo-sarcomeric localization in developing cardiomyocytes. ANKRD1 transgenic mice present sinus venosus defect, which originates during development by impaired remodelling of early embryonic heart. Adult transgenic hearts develop diastolic dysfunction with preserved ejection fraction, which progressively evolves into heart failure, as shown histologically and haemodynamically. Transgenic cardiomyocyte structure, sarcomeric assembly, and stability are progressively impaired from embryonic to adult life. Postnatal transgenic myofibrils also present characteristic functional alterations: impaired compliance at neonatal stage and impaired lusitropism in adult hearts. Altogether, our combined analyses suggest that impaired embryonic remodelling and adult heart dysfunction in ANKRD1 transgenic mice present a common ground of initial cardiomyocyte defects, which are exacerbated postnatally. Molecular analysis showed transient activation of GATA4-Nkx2.5 transcription in early transgenic embryos and subsequent dynamic transcriptional modulation within titin gene.Conclusions ANKRD1 is a fine mediator of cardiomyocyte response to haemodynamic load in the developing and adult heart. Increased ANKRD1 levels are sufficient to initiate an altered cellular phenotype, which is progressively exacerbated into a pathological organ response by the high ventricular workload during postnatal life. Our study defines for the first time a unifying picture f

Published
2020

8. An international registry for emergent pathogens and pregnancy

Author

Alice Panchaud, Guillaume Favre, Leo Pomar, Manon Vouga, Karoline Aebi-Popp, David Baud, Tallarek Ann-Christin, Strizek Brigitte, Hecher Kurt, Böckenhoff Paul, Schrey-Petersen Susanne, Mullins Edward, Bromley Rebecca, Whitehead Clare, Rolnik Daniel, Deprest Jan, Richter Jute, Gomes Luz Adriana, Bohrer Betania, Carvalho Ribeiro-do-Valle Carolina, Garanhani Surita Fernanda, Schuler-Faccini Lavinia, Osorio Wender Maria Celeste, Da Rocha Oppermann Maria Lucia, Moreira de sa Renato Augusto, Quintana Silvana, Sjaus Ana, Rahman Arifa, Hamel-Thibault Audrey, Nash Christopher, Kakkar Fatima, Berger Howard, Boucoiran Isabelle, Pasquier Jean-Charles, Snelgrove John, Zipursky Jonathan, Lacroix Meagan, Whittle Wendy, Fuenzalida Javiera, Carvajal Jorge, Guerra Canales Manuel, Hernandez Olivia, Yin Mingzhu, Chen Xiang, Qi Xiaolong, Sanín Blair José Enrique, Gonzalez Ricardo, Cano Aguilar Africa, Rodriguez Vicente Agueda, Tubau Navarra Albert, Puertas Prieto Alberto, Cano Garcia Alejandra Maria, Carrascal Cumplido Ana, Villalba Yarza Ana, Filloy Lavia Ana Cristina, Fernandez Alonso Ana Maria, Sanchez Vegazo Garcia Angeles, Goncé Anna, Ruano Garcia Antonio, Sanchez Munoz Antonio, Marcos Puig Beatriz, Munoz Abellana Begona, Garrido Luque Belen, Fernandez Fernandez Camino, Larranaga Azcarate Carlos, Baena Luque Carmen, Orizales Lago Carmen Maria, Alvarez Colomo Cristina, Lesmes Heredia Cristina, Ruiz Aguilar Cristina, Ferriols Perez Elena, Pascual Salvador Elena, Carmona Sanchez Encarnacion, Alvarez Silvares Esther, Canedo Carballeira Esther Maria, Moran Antolin Eva, Muelas Parraga Eva Maria, Oviedo Perez Eva Maria, Gonzalez Carvajal Francisco Jesus, Agudo Iène, Ocerin Bengoa Iratxe, Gastaca Abasolo Irene, Cabello de Alba Fernandez Isabel, Alvarez Javier, Duro Gomez Jorge, Atxotegi Jose, Navarrina Martinez José, Ruiz Aragon José, Sainz Bueno José Antonio, Adanez Garcia Jose Manuel, Broullon Molanes José Roman, Wizner de Alva Juan Carlos, Forcen Acebal Laura, Gonzalez Rodriguez Laura, Aceituno Velasco Longinos, Cerrillos Gonzalez Lucas, Trigo Lucas, Diaz Meca Lucia, Parada Millan M Carmen, Molina Oller Magdalena, Dominguez Gonzalez Manuel, Munoz Chapuli Gutierrez Mar, Caridad Ortiz Herrera Maria, Nieves Quesada Fernandez Maria, Suarez Arana Maria, Teulon Gonzalez Maria, Zafra Bailera Maria, Duenas Carazo Maria Begona, Gonzalez Macias Maria Carmen, Pilar Guadix Martin Maria del, Barbancho Lopez Maria del Carmen, Medina Mallen Maria del Carmen, Pardo Pumar Maria Isabel, Gimeno Gimeno Maria Joaquina, Nunez Valera Maria José, Pelegay Escartin Maria José, Camacho Caro Marta, Garcia Sanchez Marta, Meca Casbas Marta Ruth, Fraca Padilla Mercedes, Ramirez Gomez Mercedes, Catalina Coello Monica, Cruz Lemini Monica, Perez Perez Noelia, Nieto Velasco Olga, Alomar Mateu Onofre, Martinez Perez Oscar, Vaquerizo Ruiz Oscar, Barrio Fernández Pablo Guillermo del, Monteliu Gonzalez Pilar, Prats Rodriguez Pilar, Vivaracho Terrer Porfirio, Gonzales Seoane Raquel, Jimenez Velazquez Raquel, Alvarez Fernandez Rebeca, Lopez Perez Rocio, Ostos Serna Rosa Maria, Redondo Aguilar Rosario, Bernardo Vega Rut, Cano Sandra, Mateos Lopez Silvia, Fernandez Garcia Susana, Soldevilla Perez Susana, Manrique Gomez Tania, Munoz Carmona Vitor, Ko Albert I, Johnson Anthony, Nielsen Saines Karin, Cambou Mary, Grechukhina Olga, Neupane Sahara, Reddy Uma, Shah Zubin, Breton Bénédicte, Garabedian Charles, Bertholdt Charline, Poncelet Christophe, Subtil Damien, Musso Didier, Henry Estelle, Plantefeve Gaetan, Ducarme Guillaume, Pelerin Helene, Dimet Jerome, Cottin Judith, Stiremann Julien, Lambert Véronique, Hcini Najeh, Salomon Laurent, Sentilhes Loïc, Giral Marylene, Mottet Nicolas, Morel Olivier, Rozenberg Patrick, Lucie Sedille, Quibel Thibaud, Karagianni Vasiliki, Equy Véronique, Ville Yves, Carles Gabriel, Ruehl Ina, Cleary Brian, Malone Fergal, Higgins Mary, Geary Michael, Hadar Eran, Malinger Gustavo, Sela Hen, Krajden Haratz Karina, Maymon Ron, Yogev Yariv, De Luca Carmen, De Santis Marco, Rosso Telefono, Atallah David, Boguziene Emilija, Germes Pina Fernando, Van den Akker Thomas, Gil-Guevara Enrique, Marchena Jeannette, Ventura Walter, Pereira Alcides, Ayres de Campos Diogo, Charepe Nadia, Viana Pinto Pedro, Ntasumbumuyange Diomede, Rulisa Stephen, Panchaud Alice, Radan Anda-Petronela, Papadia Andrea, Bloch Andrea, Feki Anis, Muller Brochut Anne-Claude, Toussaint Arnaud, Eggel-Hort Béatrice, Martinez de Tejada Begoña, Frey Tirri Brigitte, Weber Brigitte, Blume Carolin, Monod Cécile, Kahlert Christian, Voekt Cora, Surbek Daniel, Baud David, Bassler Dirk, Mueller Doris, Prentl Elke Barbara, Gerber Eva, Rothe Friederike, Eric Giannoni, Favre Guillaume, Hoesli Irene, Mathis Jérôme, Lepigeon Karine, Aebi-Popp Karoline, Pomar Leo, Schäffer Leonhard, Raio Luigi, Vouga Manon, Huesler Charles Margaret, Rossier Marie-Claude, Hodel Markus, Kaufmann Martin, Gavillet Mathilde, Boulvain Michel, Todesco Bernasconi Monya, Bickle Myriam, Ochsenbein Kölble Nicole, Jarrah Omar, Kanellos Panagiotis, Brasier Lutz Pascale, Capoccia Brugger Romina, Heldstab Sandra, Heldstab Sandra Andrea, Rouiller Cornu Sylvie, Fischer Tina, Winterfeld Ursula, Lambelet Valentine, Rieder Wawrzyniec, Greub Gilbert, Gengler Carole, Patel Rena C, Huespe Miguel Angel, Nieto-Calvache Albaro José, COVI-Preg group, Ann-Christin, T., Brigitte, S., Kurt, H., Paul, B., Susanne, S.P., Edward, M., Rebecca, B., Clare, W., Daniel, R., Jan, D., Jute, R., Adriana, G.L., Betania, B., Carolina, C.R., Fernanda, G.S., Lavinia, S.F., Maria Celeste, O.W., Maria Lucia, DRO, Renato Augusto, M.S., Silvana, Q., Ana, S., Arifa, R., Audrey, H.T., Christopher, N., Fatima, K., Howard, B., Isabelle, B., Jean-Charles, P., John, S., Jonathan, Z., Meagan, L., Wendy, W., Javiera, F., Jorge, C., Manuel, G.C., Olivia, H., Mingzhu, Y., Xiang, C., Xiaolong, Q., José Enrique, S.B., Ricardo, G., Africa, C.A., Agueda, R.V., Albert, T.N., Alberto, P.P., Alejandra Maria, C.G., Ana, C.C., Ana, V.Y., Ana Cristina, F.L., Ana Maria, F.A., Angeles, SVG, Anna, G., Antonio, R.G., Antonio, S.M., Beatriz, M.P., Begona, M.A., Belen, G.L., Camino, F.F., Carlos, L.A., Carmen, B.L., Carmen Maria, O.L., Cristina, A.C., Cristina, L.H., Cristina, R.A., Elena, F.P., Elena, P.S., Encarnacion, C.S., Esther, A.S., Esther Maria, C.C., Eva, M.A., Eva Maria, M.P., Eva Maria, O.P., Francisco Jesus, G.C., Iène, A., Iratxe, O.B., Irene, G.A., Isabel, CAF, Javier, A., Jorge, D.G., Jose, A., José, N.M., José, R.A., José Antonio, S.B., Jose Manuel, A.G., José Roman, B.M., Juan Carlos, W.A., Laura, F.A., Laura, G.R., Longinos, A.V., Lucas, C.G., Lucas, T., Lucia, D.M., M Carmen, P.M., Magdalena, M.O., Manuel, D.G., Mar, MCG, Maria, COH, Maria, NQF, Maria, S.A., Maria, T.G., Maria, Z.B., Maria Begona, D.C., Maria Carmen, G.M., Maria Del, PGM, Maria Del Carmen, B.L., Maria Del Carmen, M.M., Maria Isabel, P.P., Maria Joaquina, G.G., Maria José, N.V., Maria José, P.E., Marta, C.C., Marta, G.S., Marta Ruth, M.C., Mercedes, F.P., Mercedes, R.G., Monica, C.C., Monica, C.L., Noelia, P.P., Olga, N.V., Onofre, A.M., Oscar, M.P., Oscar, V.R., Pablo Guillermo Del, B.F., Pilar, M.G., Pilar, P.R., Porfirio, V.T., Raquel, G.S., Raquel, J.V., Rebeca, A.F., Rocio, L.P., Rosa Maria, O.S., Rosario, R.A., Rut, B.V., Sandra, C., Silvia, M.L., Susana, F.G., Susana, S.P., Tania, M.G., Vitor, M.C., Albert I, K., Anthony, J., Karin, N.S., Mary, C., Olga, G., Sahara, N., Uma, R., Zubin, S., Bénédicte, B., Charles, G., Charline, B., Christophe, P., Damien, S., Didier, M., Estelle, H., Gaetan, P., Guillaume, D., Helene, P., Jerome, D., Judith, C., Julien, S., Véronique, L., Najeh, H., Laurent, S., Loïc, S., Marylene, G., Nicolas, M., Olivier, M., Patrick, R., Sedille, L., Thibaud, Q., Vasiliki, K., Véronique, E., Yves, V., Gabriel, C., Ina, R., Brian, C., Fergal, M., Mary, H., Michael, G., Eran, H., Gustavo, M., Hen, S., Karina, K.H., Ron, M., Yariv, Y., Carmen, L., Marco, S., Telefono, R., David, A., Emilija, B., Fernando, G.P., Thomas, VDA, Enrique, G.G., Jeannette, M., Walter, V., Alcides, P., Diogo, A.C., Nadia, C., Pedro, V.P., Diomede, N., Stephen, R., Alice, P., Anda-Petronela, R., Andrea, P., Andrea, B., Anis, F., Anne-Claude, M.B., Arnaud, T., Béatrice, E.H., Begoña, M.T., Brigitte, F.T., Brigitte, W., Carolin, B., Cécile, M., Christian, K., Cora, V., Daniel, S., David, B., Dirk, B., Doris, M., Elke Barbara, P., Eva, G., Friederike, R., Giannoni, E., Guillaume, F., Irene, H., Jérôme, M., Karine, L., Karoline, A.P., Leo, P., Leonhard, S., Luigi, R., Manon, V., Margaret, H.C., Marie-Claude, R., Markus, H., Martin, K., Mathilde, G., Michel, B., Monya, T.B., Myriam, B., Nicole, O.K., Omar, J., Panagiotis, K., Pascale, B.L., Romina, C.B., Sandra, H., Sandra Andrea, H., Sylvie, R.C., Tina, F., Ursula, W., Valentine, L., Wawrzyniec, R., Gilbert, G., Carole, G., Rena C, P., Miguel Angel, H., and Albaro José, N.C.

Subjects
Diagnostic Screening Programs, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Severe Acute Respiratory Syndrome, Communicable Diseases, Emerging, Risk Assessment, Betacoronavirus, Fetus, Pregnancy, Risk Factors, Pandemic, medicine, Humans, Registries, 610 Medicine & health, Intensive care medicine, Pandemics, Zika Virus Infection, Viral Epidemiology, business.industry, Pregnancy Outcome, Betacoronavirus/growth & development, Betacoronavirus/immunology, Communicable Diseases, Emerging/epidemiology, Communicable Diseases, Emerging/prevention & control, Coronavirus Infections/epidemiology, Diagnostic Screening Programs/standards, Female, Interdisciplinary Placement/methods, Pneumonia, Viral/epidemiology, Pregnancy Outcome/epidemiology, Severe Acute Respiratory Syndrome/epidemiology, Zika Virus/immunology, Zika Virus Infection/epidemiology, COVID-19, Zika Virus, General Medicine, medicine.disease, Interdisciplinary Placement, sars-cov-2, Settore MED/40 - GINECOLOGIA E OSTETRICIA, Coronavirus Infections, business
Published
2020

9. Human stem cell-based retina on chip as new translational model for validation of AAV retinal gene therapy vectors.

Author

Achberger K, Cipriano M, Düchs MJ, Schön C, Michelfelder S, Stierstorfer B, Lamla T, Kauschke SG, Chuchuy J, Roosz J, Mesch L, Cora V, Pars S, Pashkovskaia N, Corti S, Hartmann SM, Kleger A, Kreuz S, Maier U, Liebau S, and Loskill P

Subjects
Biomarkers, Cell Culture Techniques, Cell Culture Techniques, Three Dimensional, Cell Differentiation, Fluorescent Antibody Technique, Gene Expression, Genes, Reporter, Genetic Therapy, Humans, Organoids cytology, Retina cytology, Transgenes, Dependovirus genetics, Genetic Vectors genetics, Induced Pluripotent Stem Cells cytology, Lab-On-A-Chip Devices, Organoids metabolism, Retina metabolism, Transduction, Genetic
Abstract

Gene therapies using adeno-associated viruses (AAVs) are among the most promising strategies to treat or even cure hereditary and acquired retinal diseases. However, the development of new efficient AAV vectors is slow and costly, largely because of the lack of suitable non-clinical models. By faithfully recreating structure and function of human tissues, human induced pluripotent stem cell (iPSC)-derived retinal organoids could become an essential part of the test cascade addressing translational aspects. Organ-on-chip (OoC) technology further provides the capability to recapitulate microphysiological tissue environments as well as a precise control over structural and temporal parameters. By employing our recently developed retina on chip that merges organoid and OoC technology, we analyzed the efficacy, kinetics, and cell tropism of seven first- and second-generation AAV vectors. The presented data demonstrate the potential of iPSC-based OoC models as the next generation of screening platforms for future gene therapeutic studies., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2021
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10. Myocardial overexpression of ANKRD1 causes sinus venosus defects and progressive diastolic dysfunction.

Author

Piroddi N, Pesce P, Scellini B, Manzini S, Ganzetti GS, Badi I, Menegollo M, Cora V, Tiso S, Cinquetti R, Monti L, Chiesa G, Bleyl SB, Busnelli M, Dellera F, Bruno D, Caicci F, Grimaldi A, Taramelli R, Manni L, Sacerdoti D, Tesi C, Poggesi C, Ausoni S, Acquati F, and Campione M

Subjects
Animals, Diastole, Female, GATA4 Transcription Factor genetics, GATA4 Transcription Factor metabolism, Gene Expression Regulation, Developmental, Heart Septal Defects, Atrial genetics, Heart Septal Defects, Atrial pathology, Heart Septal Defects, Atrial physiopathology, Homeobox Protein Nkx-2.5 genetics, Homeobox Protein Nkx-2.5 metabolism, Male, Mice, Transgenic, Muscle Proteins genetics, Myocardium pathology, Nuclear Proteins genetics, Protein Kinases genetics, Protein Kinases metabolism, Repressor Proteins genetics, Up-Regulation, Ventricular Dysfunction, Left genetics, Ventricular Dysfunction, Left pathology, Ventricular Dysfunction, Left physiopathology, Heart Septal Defects, Atrial metabolism, Muscle Proteins metabolism, Myocardium metabolism, Nuclear Proteins metabolism, Repressor Proteins metabolism, Ventricular Dysfunction, Left metabolism, Ventricular Function, Left
Abstract

Aims: Increased Ankyrin Repeat Domain 1 (ANKRD1) levels linked to gain of function mutations have been associated to total anomalous pulmonary venous return and adult cardiomyopathy occurrence in humans. The link between increased ANKRD1 level and cardiac structural and functional disease is not understood. To get insight into this problem, we have generated a gain of function ANKRD1 mouse model by overexpressing ANKRD1 in the myocardium., Methods and Results: Ankrd1 is expressed non-homogeneously in the embryonic myocardium, with a dynamic nucleo-sarcomeric localization in developing cardiomyocytes. ANKRD1 transgenic mice present sinus venosus defect, which originates during development by impaired remodelling of early embryonic heart. Adult transgenic hearts develop diastolic dysfunction with preserved ejection fraction, which progressively evolves into heart failure, as shown histologically and haemodynamically. Transgenic cardiomyocyte structure, sarcomeric assembly, and stability are progressively impaired from embryonic to adult life. Postnatal transgenic myofibrils also present characteristic functional alterations: impaired compliance at neonatal stage and impaired lusitropism in adult hearts. Altogether, our combined analyses suggest that impaired embryonic remodelling and adult heart dysfunction in ANKRD1 transgenic mice present a common ground of initial cardiomyocyte defects, which are exacerbated postnatally. Molecular analysis showed transient activation of GATA4-Nkx2.5 transcription in early transgenic embryos and subsequent dynamic transcriptional modulation within titin gene., Conclusions: ANKRD1 is a fine mediator of cardiomyocyte response to haemodynamic load in the developing and adult heart. Increased ANKRD1 levels are sufficient to initiate an altered cellular phenotype, which is progressively exacerbated into a pathological organ response by the high ventricular workload during postnatal life. Our study defines for the first time a unifying picture for ANKRD1 role in heart development and disease and provides the first mechanistic link between ANKRD1 overexpression and cardiac disease onset., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Published
2020
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11. Using Transcriptomic Analysis to Assess Double-Strand Break Repair Activity: Towards Precise in vivo Genome Editing.

Author

Pasquini G, Cora V, Swiersy A, Achberger K, Antkowiak L, Müller B, Wimmer T, Fraschka SA, Casadei N, Ueffing M, Liebau S, Stieger K, and Busskamp V

Subjects
Adult, Animals, Cell Cycle genetics, Gene Expression Regulation, Genome, Humans, Induced Pluripotent Stem Cells metabolism, Mammals genetics, Mice, Photoreceptor Cells, Vertebrate metabolism, DNA Breaks, Double-Stranded, DNA Repair genetics, Gene Editing, Gene Expression Profiling
Abstract

Mutations in more than 200 retina-specific genes have been associated with inherited retinal diseases. Genome editing represents a promising emerging field in the treatment of monogenic disorders, as it aims to correct disease-causing mutations within the genome. Genome editing relies on highly specific endonucleases and the capacity of the cells to repair double-strand breaks (DSBs). As DSB pathways are cell-cycle dependent, their activity in postmitotic retinal neurons, with a focus on photoreceptors, needs to be assessed in order to develop therapeutic in vivo genome editing. Three DSB-repair pathways are found in mammalian cells: Non-homologous end joining (NHEJ); microhomology-mediated end joining (MMEJ); and homology-directed repair (HDR). While NHEJ can be used to knock out mutant alleles in dominant disorders, HDR and MMEJ are better suited for precise genome editing, or for replacing entire mutation hotspots in genomic regions. Here, we analyzed transcriptomic in vivo and in vitro data and revealed that HDR is indeed downregulated in postmitotic neurons, whereas MMEJ and NHEJ are active. Using single-cell RNA sequencing analysis, we characterized the dynamics of DSB repair pathways in the transition from dividing cells to postmitotic retinal cells. Time-course bulk RNA-seq data confirmed DSB repair gene expression in both in vivo and in vitro samples. Transcriptomic DSB repair pathway profiles are very similar in adult human, macaque, and mouse retinas, but not in ground squirrel retinas. Moreover, human-induced pluripotent stem-cell-derived neurons and retinal organoids can serve as well suited in vitro testbeds for developing genomic engineering approaches in photoreceptors. Our study provides additional support for designing precise in vivo genome-editing approaches via MMEJ, which is active in mature photoreceptors., Competing Interests: The authors declare no conflict of interest.

Published
2020
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12. Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform.

Author

Achberger K, Probst C, Haderspeck J, Bolz S, Rogal J, Chuchuy J, Nikolova M, Cora V, Antkowiak L, Haq W, Shen N, Schenke-Layland K, Ueffing M, Liebau S, and Loskill P

Subjects
Humans, Induced Pluripotent Stem Cells physiology, Lab-On-A-Chip Devices, Organoids growth & development, Retina physiology
Abstract

The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration or retinitis pigmentosa urgently require the development of new therapeutic strategies. Additionally, a high prevalence of retinal toxicities is becoming more and more an issue of novel targeted therapeutic agents. Ophthalmologic drug development, to date, largely relies on animal models, which often do not provide results that are translatable to human patients. Hence, the establishment of sophisticated human tissue-based in vitro models is of upmost importance. The discovery of self-forming retinal organoids (ROs) derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) is a promising approach to model the complex stratified retinal tissue. Yet, ROs lack vascularization and cannot recapitulate the important physiological interactions of matured photoreceptors and the retinal pigment epithelium (RPE). In this study, we present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell types derived from hiPSCs. It provides vasculature-like perfusion and enables, for the first time, the recapitulation of the interaction of mature photoreceptor segments with RPE in vitro. We show that this interaction enhances the formation of outer segment-like structures and the establishment of in vivo-like physiological processes such as outer segment phagocytosis and calcium dynamics. In addition, we demonstrate the applicability of the RoC for drug testing, by reproducing the retinopathic side-effects of the anti-malaria drug chloroquine and the antibiotic gentamicin. The developed hiPSC-based RoC has the potential to promote drug development and provide new insights into the underlying pathology of retinal diseases., Competing Interests: KA, CP, JH, SB, JR, JC, MN, VC, LA, WH, NS, KS, MU, SL, PL No competing interests declared, (© 2019, Achberger et al.)

Published
2019
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13. A Cleared View on Retinal Organoids.

Author

Cora V, Haderspeck J, Antkowiak L, Mattheus U, Neckel PH, Mack AF, Bolz S, Ueffing M, Pashkovskaia N, Achberger K, and Liebau S

Subjects
Alcohol Oxidoreductases chemistry, Cell Culture Techniques methods, Co-Repressor Proteins chemistry, Humans, Organ Culture Techniques methods, Tissue Engineering methods, Induced Pluripotent Stem Cells ultrastructure, Organoids growth & development, Organoids ultrastructure, Photoreceptor Cells ultrastructure, Retina ultrastructure
Abstract

Human induced pluripotent stem cell (hiPSC)-derived organoids mimicking tissues and organs in vitro have advanced medical research, as they opened up new possibilities for in-depth basic research on human organ development as well as providing a human in vitro model for personalized therapeutic approaches. hiPSC-derived retinal organoids have proven to be of great value for modeling the human retina featuring a very similar cellular composition, layering, and functionality. The technically challenging imaging of three-dimensional structures such as retinal organoids has, however, raised the need for robust whole-organoid imaging techniques. To improve imaging of retinal organoids we optimized a passive clearing technique (PACT), which enables high-resolution visualization of fragile intra-tissue structures. Using cleared retinal organoids, we could greatly enhance the antibody labeling efficiency and depth of imaging at high resolution, thereby improving the three-dimensional microscopy output. In that course, we were able to identify the spatial morphological shape and organization of, e.g., photoreceptor cells and bipolar cell layers. Moreover, we used the synaptic protein CtBP2/Ribeye to visualize the interconnection points of photoreceptor and bipolar cells forming the retinal-specific ribbon synapses.

Published
2019
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