A novel 3D label-free monitoring system of hES-derived cardiomyocyte clusters: a step forward to in vitro cardiotoxicity testing
Unexpected adverse effects on the cardiovascular system remain a major challenge in the development of novel active pharmaceutical ingredients (API). To overcome the current limitations of animal-based in vitro and in vivo test systems, stem cell derived human cardiomyocyte clusters (hCMC) offer the...
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| Veröffentlicht in: | PloS one 2013-07, Vol.8 (7), p.e68971 |
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| creator | Jahnke, Heinz-Georg Steel, Daniella Fleischer, Stephan Seidel, Diana Kurz, Randy Vinz, Silvia Dahlenborg, Kerstin Sartipy, Peter Robitzki, Andrea A |
| description | Unexpected adverse effects on the cardiovascular system remain a major challenge in the development of novel active pharmaceutical ingredients (API). To overcome the current limitations of animal-based in vitro and in vivo test systems, stem cell derived human cardiomyocyte clusters (hCMC) offer the opportunity for highly predictable pre-clinical testing. The three-dimensional structure of hCMC appears more representative of tissue milieu than traditional monolayer cell culture. However, there is a lack of long-term, real time monitoring systems for tissue-like cardiac material. To address this issue, we have developed a microcavity array (MCA)-based label-free monitoring system that eliminates the need for critical hCMC adhesion and outgrowth steps. In contrast, feasible field potential derived action potential recording is possible immediately after positioning within the microcavity. Moreover, this approach allows extended observation of adverse effects on hCMC. For the first time, we describe herein the monitoring of hCMC over 35 days while preserving the hCMC structure and electrophysiological characteristics. Furthermore, we demonstrated the sensitive detection and quantification of adverse API effects using E4031, doxorubicin, and noradrenaline directly on unaltered 3D cultures. The MCA system provides multi-parameter analysis capabilities incorporating field potential recording, impedance spectroscopy, and optical read-outs on individual clusters giving a comprehensive insight into induced cellular alterations within a complex cardiac culture over days or even weeks. |
| doi_str_mv | 10.1371/journal.pone.0068971 |
| format | Article |
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To overcome the current limitations of animal-based in vitro and in vivo test systems, stem cell derived human cardiomyocyte clusters (hCMC) offer the opportunity for highly predictable pre-clinical testing. The three-dimensional structure of hCMC appears more representative of tissue milieu than traditional monolayer cell culture. However, there is a lack of long-term, real time monitoring systems for tissue-like cardiac material. To address this issue, we have developed a microcavity array (MCA)-based label-free monitoring system that eliminates the need for critical hCMC adhesion and outgrowth steps. In contrast, feasible field potential derived action potential recording is possible immediately after positioning within the microcavity. Moreover, this approach allows extended observation of adverse effects on hCMC. For the first time, we describe herein the monitoring of hCMC over 35 days while preserving the hCMC structure and electrophysiological characteristics. Furthermore, we demonstrated the sensitive detection and quantification of adverse API effects using E4031, doxorubicin, and noradrenaline directly on unaltered 3D cultures. The MCA system provides multi-parameter analysis capabilities incorporating field potential recording, impedance spectroscopy, and optical read-outs on individual clusters giving a comprehensive insight into induced cellular alterations within a complex cardiac culture over days or even weeks.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0068971</identifier><identifier>PMID: 23861955</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Action potential ; Analysis ; Biology ; Biotechnology ; Cardiac arrhythmia ; Cardiomyocytes ; Cardiotoxicity ; Cardiotoxins - toxicity ; Cardiovascular system ; Cell Aggregation - drug effects ; Cell culture ; Chemotherapy ; Clusters ; Doxorubicin ; Electrophysiological Phenomena - drug effects ; Embryonic Stem Cells - cytology ; Embryonic Stem Cells - drug effects ; Heart ; Heart diseases ; Humans ; In vitro methods and tests ; In vivo methods and tests ; Medicine ; Monitoring ; Monomolecular films ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - drug effects ; Noradrenaline ; Norepinephrine ; Recording ; Side effects ; Signal Processing, Computer-Assisted ; Spectroscopy ; Staining and Labeling ; Stem cells ; Studies ; Time Factors</subject><ispartof>PloS one, 2013-07, Vol.8 (7), p.e68971</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Jahnke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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To overcome the current limitations of animal-based in vitro and in vivo test systems, stem cell derived human cardiomyocyte clusters (hCMC) offer the opportunity for highly predictable pre-clinical testing. The three-dimensional structure of hCMC appears more representative of tissue milieu than traditional monolayer cell culture. However, there is a lack of long-term, real time monitoring systems for tissue-like cardiac material. To address this issue, we have developed a microcavity array (MCA)-based label-free monitoring system that eliminates the need for critical hCMC adhesion and outgrowth steps. In contrast, feasible field potential derived action potential recording is possible immediately after positioning within the microcavity. Moreover, this approach allows extended observation of adverse effects on hCMC. For the first time, we describe herein the monitoring of hCMC over 35 days while preserving the hCMC structure and electrophysiological characteristics. Furthermore, we demonstrated the sensitive detection and quantification of adverse API effects using E4031, doxorubicin, and noradrenaline directly on unaltered 3D cultures. 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To overcome the current limitations of animal-based in vitro and in vivo test systems, stem cell derived human cardiomyocyte clusters (hCMC) offer the opportunity for highly predictable pre-clinical testing. The three-dimensional structure of hCMC appears more representative of tissue milieu than traditional monolayer cell culture. However, there is a lack of long-term, real time monitoring systems for tissue-like cardiac material. To address this issue, we have developed a microcavity array (MCA)-based label-free monitoring system that eliminates the need for critical hCMC adhesion and outgrowth steps. In contrast, feasible field potential derived action potential recording is possible immediately after positioning within the microcavity. Moreover, this approach allows extended observation of adverse effects on hCMC. For the first time, we describe herein the monitoring of hCMC over 35 days while preserving the hCMC structure and electrophysiological characteristics. Furthermore, we demonstrated the sensitive detection and quantification of adverse API effects using E4031, doxorubicin, and noradrenaline directly on unaltered 3D cultures. The MCA system provides multi-parameter analysis capabilities incorporating field potential recording, impedance spectroscopy, and optical read-outs on individual clusters giving a comprehensive insight into induced cellular alterations within a complex cardiac culture over days or even weeks.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23861955</pmid><doi>10.1371/journal.pone.0068971</doi><tpages>e68971</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Action potential Analysis Biology Biotechnology Cardiac arrhythmia Cardiomyocytes Cardiotoxicity Cardiotoxins - toxicity Cardiovascular system Cell Aggregation - drug effects Cell culture Chemotherapy Clusters Doxorubicin Electrophysiological Phenomena - drug effects Embryonic Stem Cells - cytology Embryonic Stem Cells - drug effects Heart Heart diseases Humans In vitro methods and tests In vivo methods and tests Medicine Monitoring Monomolecular films Myocytes, Cardiac - cytology Myocytes, Cardiac - drug effects Noradrenaline Norepinephrine Recording Side effects Signal Processing, Computer-Assisted Spectroscopy Staining and Labeling Stem cells Studies Time Factors |
| title | A novel 3D label-free monitoring system of hES-derived cardiomyocyte clusters: a step forward to in vitro cardiotoxicity testing |
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