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Functional characterization and comparison of stem cell-derived cardiomyocytes for cardiac regenerative medicine

Applicant Ullrich Nina
Number 131987
Funding scheme Ambizione
Research institution Institut für Physiologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.01.2011 - 30.06.2014
Approved amount 583'605.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Physiology : other topics

Keywords (8)

excitation-contraction coupling; stem cell; cardiomyocyte; ion channel; Calcium signaling; integration; heart; development

Lay Summary (German)

Lead
Lay summary
Chronische Herzkrankheiten und Herzinfarkt führen zu starker Beeinträchtigung der Herzmuskelfunktion. In der kardiogenen Stammzellforschung werden aus Stammzellen herzähnliche Zellen entwickelt, die im Zuge einer Zelltransplantation die Herzleistung verbessern sollen. In diesem Projekt werden die funktionellen Eigenschaften dieser Herzzellen untersucht.

Neben den ultimativen Ziel der Transplantation liegt ein großes Interesse der Stammzellforschung auch darin, Zellmodelle zu kreieren, um bestimmte Krankheiten zu untersuchen, aber auch für schnelles Wirkstoff-Screening in der pharmazeutischen Anwendung. Diese Zellmodelle könnten in Zukunft die Notwendigkeit für Tiermodelle reduzieren, einen besseren (humanen) Hintergrund für die Untersuchung bestimmter Krankheiten gewährleisten und die Übertragbarkeit der Resultate auf menschliche Anwendungen beschleunigen. Derzeit sind bereits Herzzellen diverser pluri- oder multipotenter Quellen im Einsatz für klinische Studien der kardiovaskulären Regenerativmedizin, und zwar trotz vieler ungeklärter Fragen bezüglich Funktionstüchtigkeit und Nutzen für bestimmte Herzerkrankungen. Die Untersuchung der elektrischen und mechanischen Eigenschaften dieser Zellen stehen daher im Zentrum dieses Projekts.

In Herzmuskelzellen ist das zelluläre Kalziumsignalsystem massgebend für die Kontraktilität der Zelle und die Kraftentwicklung während der Muskelkontraktion. In diesem Projekt werden wir die bioelektrischen Eigenschaften der aus Stammzellen gezüchteten Herzzellen untersuchen und mithilfe bildgebender Verfahren die Physiologie der Kalziumsignale während elektrischer Erregung untersuchen. Wir testen die Hypothese, dass aus Stammzellen gezüchtete Herzzellen ähnliche physiologische Erregungs-Kontraktionsmechanismen entwickeln wie adulte Herzmuskelzellen und funktionell miteinander in Verbindung stehen können.

Die aus Stammzellen gewonnenen herzähnlichen Zellen sollen in der Transplantationsmedizin eingesetzt werden, wo diese Zellen in Herzen von Infarktpatienten oder Patienten mit Herzschwäche injiziert werden, um die beeinträchtigte Herzfunktion zu verbessern. Es ist natürlich unerlässlich, im Vorfeld die genauen Funktionen dieser Zellen (einzeln, sowie im Zellverband) zu kennen und ihren Nutzen, wie auch mögliche Komplikationen kritisch unter allen physiologischen Bedingungen getestet zu haben, bevor diese Zellen systematisch für klinische Studien herangezogen werden können. Das vorliegende Projekt dient genau dieser detaillierten Charakterisierung und wird einen wichtigen Beitrag für die Erforschung von Stammzellen und ihren Nutzen für die klinische Regenerativmedizin liefern.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
CULTURE OF CARDIOGENIC STEM CELLS ON PCL-SCAFFOLDS: TOWARDS THE CREATION OF BEATING TISSUE CONSTRUCTS
Guex A.G., Romano F., Marcu I.C., Tevaearai H.T., Ullrich N.D., Giraud M.N. (2013), CULTURE OF CARDIOGENIC STEM CELLS ON PCL-SCAFFOLDS: TOWARDS THE CREATION OF BEATING TISSUE CONSTRUCTS, in ACTA Press.
Isolation of Cardiovascular Precursor Cells from the Human Fetal Heart.
Gonzales Christine, Ullrich Nina D, Gerber Stefan, Berthonneche Corinne, Niggli Ernst, Pedrazzini Thierry (2011), Isolation of Cardiovascular Precursor Cells from the Human Fetal Heart., in Tissue engineering. Part A, 18(1-2), 198-207.

Collaboration

Group / person Country
Types of collaboration
Universität Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Universität Bern, Inselspital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
KIT Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Universität Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Novartis Pharma AG Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Universität Genf Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gordon Conference Cardiac Regulatory Mechanisms Talk given at a conference Functional characterization of stem cell-derived cardiomyocytes: a comparative study of intercellular communication 08.06.2014 New London, United States of America Ullrich Nina;
Deutsche Gesellschaft für Kardiologie Talk given at a conference Functional characterization of stem cell-derived cardiomyocytes 23.04.2014 Mannheim, Germany Ullrich Nina;
Deutsche Physiologen Tagung Poster Intercellular communication in stem cell-derived cardiomyocytes 13.03.2014 Mainz, Germany Ullrich Nina;
DZHK Seminare Individual talk Into the heart - novel cellular and subcellular strategies for myocardial repair 21.01.2014 Heidelberg, Germany Ullrich Nina;
IASTED International Conference on Biomedical Engineering Talk given at a conference Culture of Cardiogenic Stem Cells on PCL-Scaffolds: Towards the Creation of Beating Tissue Constructs 13.02.2013 Innsbruck, Austria, Austria Ullrich Nina;
Swiss Experimental Surgery Symposium Talk given at a conference Functional Characterization of Stem Cell-Derived Cardiomyocytes 17.01.2013 Fribourg, Switzerland, Switzerland Ullrich Nina;
Annual Congress of the German Society for Stem Cell Research Poster none 29.11.2012 Leipzig, Germany, Germany Ullrich Nina;
IUPS Poster Functional characterization of stem cell-derived cardiomyocytes: a comparative study 21.06.2012 Birmingham, Great Britain and Northern Ireland Ullrich Nina;
Frontiers in cardiac and vascular regeneration Poster Functional Characterization of Stem Cell-Derived Cardiomyocytes 30.05.2012 Trieste, Italy, Italy Marcu Irene Cristina;


Awards

Title Year
Best Paper Award 2013

Abstract

Background and Rationale:Cardiac stem cell research and stem cell (SC)-based therapy of injured cardiac muscle represent the new hope for cardiac repair after damage or disease. In recent years, reports on major advances in this field have become available, also comprising ideas and ongoing discussions on how to improve or boost the heart’s innate ability for regeneration of defect sites, and feed our anticipation of an ultimate triumph in this field. The increasing knowledge and potential of SC-derived cardiomyocytes confirm the successes of a multi-disciplinary approach combining genetical engineering, developmental and molecular biotechnology up to transplantation. Besides the final purpose of transplantation of newly engineered tissue, a major interest in stem cell research is to provide cellular models, ideally derived from (diseased) human material, not only to study certain diseases in a human model, but also for drug screening. These cell models might eventually reduce the need for animal disease models, create a better (human) background for the investigation of certain diseases and increase predictability of human applications. Currently, cardiomyocytes derived from diverse pluri- or multipotent sources are already in use for clinical trials in cardiovascular regenerative medicine despite the many open questions about their curative potential for several cardiac conditions.Even though many areas of research are largely covered in the context of cardiac SC research, explorations of basic but crucial cellular functions that SC-derived cardiomyocytes require for successful functional integration in vivo, are very limited. Only few studies have been published, where the electrical and, equally important, mechanical functioning of such cells has been characterized thoroughly and with the necessary attention to detail. However, this information is of utmost importance before such cells can be successfully used for therapeutical interventions, and such studies are therefore urgently needed. Working hypothesis:In this project, we aim to fill these gaps and focus on the following three topics: We hypothesize that 1.) single SC-derived cardiomyocytes of various origin provide all molecular determinants in order to perform excitation-contraction (EC)-coupling in a similar way as native cardiomyocytes. 2.) SC-derived cardiomyocytes can connect to other SC-derived and/or native cardiomyocytes and integrate in a functional electrical syncytium as a conductive unit. 3.) SC-derived cardiomyocytes carrying specific human disease traits represent ideal cell models for studying different causes of cardiomyopathy.General aims and experimental design: In three causally connected aims, we will investigate 1.) the electrophysiological properties of SC-derived cardiomyocytes from different sources at the single cell level and examine the Ca2+-induced Ca2+ release mechanism required to activate the contractile machinery of the myocyte. Ca2+ signals need to by highly synchronized throughout the cells, and this requires a high degree of differentiation and a very complex Ca2+ signalling system. From these data, we will determine the EC-coupling gain, which is a measure for the quality and fidelity of EC-coupling and allows functional comparison with intact adult cardiomyocytes. 2.) Intercellular electrical and metabolic coupling and communication will be studied in cell pairs and conductive monolayers. Action potential propagation and conductance velocities will be compared in two-dimensional homogeneous and heterogeneous cell layers. The effect of intercellular communication in a 3D-model will be evaluated on the level of protein expression and distribution. Electrophysiological properties of myocytes isolated from 3D-SC-cell aggregates will be compared with the respective properties of cells grown under 2D-conditions. 3.) Clear electrophysiological characterization of induced pluripotent (iP) SC-derived cardiomyocytes may ultimately allow the development of cellular models for cardiac diseases, especially arrhythmogenic diseases derived from channelopathies (LQTS, Brugada syndrome). In the course of this research program, we aim to perform initial functional evaluation of such disease-bearing SC-derived cardiac cells in the same extent as outlined above and in direct comparison with corresponding native cardiomyocytes or, if available, directly with human tissue from biopsies. Comprehensive functional evaluation of disease-bearing iPSCs may boost the development of repair mechanisms for gene therapy and autologous transplantation of genetically modified tissue.Expected value of the proposed project:Overall, with this project we hope to contribute significantly to a better understanding of key physiological properties, such as electrical-, Ca2+ signalling- and force generating peformance, of SC-derived cardiomyocytes of different sources and the quality of potential integration in native cardiac tissue.
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