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Biomaterials. 2016 Aug;98:64-78. doi: 10.1016/j.biomaterials.2016.04.003. Epub 2016 Apr 26.

Myocardial commitment from human pluripotent stem cells: Rapid production of human heart grafts.

Author information

1
Pluripotent Stem Cells and Activation of Endogenous Tissue Programs for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain.
2
Pluripotent Stem Cells and Activation of Endogenous Tissue Programs for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Center of Regenerative Medicine in Barcelona (CMRB), Barcelona, Spain.
3
Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Spain; Cell Production Unit, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañón (IiSGM), Madrid, Spain.
4
Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; University of Barcelona, Barcelona, Spain.
5
Bioartifical Organs Laboratory, Instituto de Investigación Sanitaria Hospital Gregorio Marañón (IiSGM), Madrid, Spain.
6
Biomimetic Systems for Cell Engineering, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain.
7
National Transplant Organization (ONT), Spanish Ministry of Health and Consumption, Spain.
8
Center for Cardiovascular Repair, University of Minnesota, Minneapolis, MN, USA; Department of Regenerative Medicine Research, Texas Heart Institute, Houston, TX, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
9
Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Spain; Cell Production Unit, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañón (IiSGM), Madrid, Spain. Electronic address: faviles@secardiologia.es.
10
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. Electronic address: belmonte@salk.edu.
11
Pluripotent Stem Cells and Activation of Endogenous Tissue Programs for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain. Electronic address: nmontserrat@ibecbarcelona.eu.

Abstract

Genome editing on human pluripotent stem cells (hPSCs) together with the development of protocols for organ decellularization opens the door to the generation of autologous bioartificial hearts. Here we sought to generate for the first time a fluorescent reporter human embryonic stem cell (hESC) line by means of Transcription activator-like effector nucleases (TALENs) to efficiently produce cardiomyocyte-like cells (CLCs) from hPSCs and repopulate decellularized human heart ventricles for heart engineering. In our hands, targeting myosin heavy chain locus (MYH6) with mCherry fluorescent reporter by TALEN technology in hESCs did not alter major pluripotent-related features, and allowed for the definition of a robust protocol for CLCs production also from human induced pluripotent stem cells (hiPSCs) in 14 days. hPSCs-derived CLCs (hPSCs-CLCs) were next used to recellularize acellular cardiac scaffolds. Electrophysiological responses encountered when hPSCs-CLCs were cultured on ventricular decellularized extracellular matrix (vdECM) correlated with significant increases in the levels of expression of different ion channels determinant for calcium homeostasis and heart contractile function. Overall, the approach described here allows for the rapid generation of human cardiac grafts from hPSCs, in a total of 24 days, providing a suitable platform for cardiac engineering and disease modeling in the human setting.

KEYWORDS:

Cardiac function; Extracellular matrix; Gene targeting; Pluripotent stem cells

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