Maturation of human pluripotent stem cell derived cardiomyocytes is improved in cardiovascular construct

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Abstract

In order to translate preclinical data into the clinical studies, relevant in vitro models with structure and key functional properties similar to native human tissue should be used. In vitro cardiac models with vascular structures mimic the highly vascularized myocardium and provide interactions between endothelial cells, stromal cells and cardiomyocytes. Currently, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been shown to present immature morphology and fetal-like electrophysiological properties that may limit their use as physiological test platform. The aim of this study was to develop multicellular in vitro cardiovascular construct modeling human heart tissue. In the cardiovascular construct, hPSC-CMs were cultured with a vascular-like network formed by human foreskin fibroblasts and human umbilical vein endothelial cells that served as a platform in the construct. Cardiomyocyte orientation, maturation, electrophysiological properties and drug responses of the cardiovascular construct were characterized and compared to CM monoculture. hPSC-CMs in cardiovascular construct showed elongated morphology and aligned with the vascular-like network. Electrophysiological properties and calcium metabolism of hPSC-CMs as well as response to E-4031 and adrenaline demonstrated normal physiological behavior. Increased expression of cardiac structural proteins and ion channels in cardiovascular construct compared to CM monoculture were detected. In conclusion, vascular-like network supports the structural and functional maturation of hPSC-CMs. Our results suggest that cardiovascular construct presents more mature in vitro cardiac model compared to CM monoculture and could therefore serve as an advanced test system for cardiac safety and efficacy assessment as well as a model system for biomedical research.

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The online version of this article (doi:10.1007/s10616-017-0088-1) contains supplementary material, which is available to authorized users.

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Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes.

Claire Robertson, David Tran, Steven George (2013)

Human pluripotent stem cell-derived cardiomyocytes (hPS-CM) may offer a number of advantages over previous cardiac models, however, questions of their immaturity complicate their adoption as a new in vitro model. hPS-CM differ from adult cardiomyocytes with respect to structure, proliferation, metabolism and electrophysiology, better approximating fetal cardiomyocytes. Time in culture appears to significantly impact phenotype, leading to what can be referred to as early and late hPS-CM. This work surveys the phenotype of hPS-CM, including structure, bioenergetics, sensitivity to damage, gene expression, and electrophysiology, including action potential, ion channels, and intracellular calcium stores, while contrasting fetal and adult CM with hPS-CM at early and late time points after onset of differentiation. Copyright © 2013 AlphaMed Press.

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Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes.

Stefan Braam, Leon L Tertoolen, Anja van de Stolpe … (2010)

Recent withdrawals of prescription drugs from clinical use because of unexpected side effects on the heart have highlighted the need for more reliable cardiac safety pharmacology assays. Block of the human Ether-a-go go Related Gene (hERG) ion channel in particular is associated with life-threatening arrhythmias, such as Torsade de Pointes (TdP). Here we investigated human cardiomyocytes derived from pluripotent (embryonic) stem cells (hESC) as a renewable, scalable, and reproducible system on which to base cardiac safety pharmacology assays. Analyses of extracellular field potentials in hESC-derived cardiomyocytes (hESC-CM) and generation of derivative field potential duration (FPD) values showed dose-dependent responses for 12 cardiac and noncardiac drugs. Serum levels in patients of drugs with known effects on QT interval overlapped with prolonged FPD values derived from hESC-CM, as predicted. We thus propose hESC-CM FPD prolongation as a safety criterion for preclinical evaluation of new drugs in development. This is the first study in which dose responses of such a wide range of compounds on hESC-CM have been generated and shown to be predictive of clinical effects. We propose that assays based on hESC-CM could complement or potentially replace some of the preclinical cardiac toxicity screening tests currently used for lead optimization and further development of new drugs. Copyright 2009 Elsevier B.V. All rights reserved.

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Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues.

Nicole Feric, Milica Radisic (2016)

Engineering functional human cardiac tissue that mimics the native adult morphological and functional phenotype has been a long held objective. In the last 5 years, the field of cardiac tissue engineering has transitioned from cardiac tissues derived from various animal species to the production of the first generation of human engineered cardiac tissues (hECTs), due to recent advances in human stem cell biology. Despite this progress, the hECTs generated to date remain immature relative to the native adult myocardium. In this review, we focus on the maturation challenge in the context of hECTs, the present state of the art, and future perspectives in terms of regenerative medicine, drug discovery, preclinical safety testing and pathophysiological studies.

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Author and article information

Contributors

Hanna Vuorenpää: +358405742287 , hanna.k.vuorenpaa@gmail.com

Kirsi Penttinen:

ORCID: http://orcid.org/0000-0003-1925-6420

+358401904158 , kirsi.penttinen@uta.fi

Tuula Heinonen: tuula.heinonen@staff.uta.fi

Mari Pekkanen-Mattila: mari.pekkanen-mattila@uta.fi

Jertta-Riina Sarkanen: riina.sarkanen@staff.uta.fi

Timo Ylikomi: timo.ylikomi@staff.uta.fi

Katriina Aalto-Setälä: katriina.aalto-setala@uta.fi

Journal

Journal ID (nlm-ta): Cytotechnology

Journal ID (iso-abbrev): Cytotechnology

Title: Cytotechnology

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0920-9069

ISSN (Electronic): 1573-0778

Publication date (Electronic): 10 April 2017

Publication date PMC-release: 10 April 2017

Publication date (Print): October 2017

Volume: 69

Issue: 5

Pages: 785-800

Affiliations

[1 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, FICAM, Finnish Centre for Alternative Methods, Faculty of Medicine and Life Sciences, , University of Tampere, ; PL 100, 33014 Tampere, Finland

[2 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, BioMediTech, Institute of Biomedical Technology, Faculty of Medicine and Life Sciences, , University of Tampere, ; PL 100, 33014 Tampere, Finland

[3 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Faculty of Medicine and Life Sciences, , University of Tampere, ; PL 100, 33014 Tampere, Finland

[4 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Department of Cell Biology, Faculty of Medicine and Life Sciences, , University of Tampere, ; Tampere, Finland

[5 ]ISNI 0000 0004 0628 2985, GRID grid.412330.7, Heart Hospital, , Tampere University Hospital, ; Tampere, Finland

Author information

Kirsi Penttinen http://orcid.org/0000-0003-1925-6420

Article

Publisher ID: 88

DOI: 10.1007/s10616-017-0088-1

PMC ID: 5595750

PubMed ID: 28397099

SO-VID: eda5a7f6-f51d-4430-84ed-a60e13deac67

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 4 November 2016

Date accepted : 17 March 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003406, Tekes;

Funded by: FundRef http://dx.doi.org/10.13039/501100005633, Sydäntutkimussäätiö;

Funded by: Pirkanmaa Hospital District Foundation

Funded by: FundRef http://dx.doi.org/10.13039/501100003126, Opetus- ja Kulttuuriministeriö;

Funded by: FinPharma Doctoral Programme

Funded by: FundRef http://dx.doi.org/10.13039/501100007083, Orionin Tutkimussäätiö;

Funded by: FundRef http://dx.doi.org/10.13039/501100003125, Suomen Kulttuurirahasto;

Funded by: FundRef http://dx.doi.org/10.13039/501100006697, Maa- ja MetsätalousministeriÖ;

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ScienceOpen disciplines: Biotechnology

Keywords: cardiomyocytes,vascular-like network,maturation

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ScienceOpen disciplines: Biotechnology

Keywords: cardiomyocytes, vascular-like network, maturation

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Maturation of human pluripotent stem cell derived cardiomyocytes is improved in cardiovascular construct

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Most cited references 29

Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes.

Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes.

Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues.

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Cited by 14

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