title: Acellular human heart matrix: A critical step toward whole heart grafts.
abstract: The best definitive treatment option for end-stage heart failure currently is transplantation, which is limited by donor availability and immunorejection. Generating an autologous bioartificial heart could overcome these limitations. Here, we have decellularized a human heart, preserving its 3-dimensional architecture and vascularity, and recellularized the decellularized extracellular matrix (dECM). We decellularized 39 human hearts with sodium-dodecyl-sulfate for 4-8 days. Cell removal and architectural integrity were determined anatomically, functionally, and histologically. To assess cytocompatibility, we cultured human cardiac-progenitor cells (hCPC), bone-marrow mesenchymal cells (hMSCs), human endothelial cells (HUVECs), and H9c1 and HL-1 cardiomyocytes in vitro on dECM ventricles up to 21 days. Cell survival, gene expression, organization and/or electrical coupling were analyzed and compared to conventional 2-dimensional cultures. Decellularization removed cells but preserved the 3-dimensional cardiac macro and microstructure and the native vascular network in a perfusable state. Cell survival was observed on dECM for 21 days. hCPCs and hMSCs expressed cardiocyte genes but did not adopt cardiocyte morphology or organization; HUVECs formed a lining of endocardium and vasculature; differentiated cardiomyocytes organized into nascent muscle bundles and displayed mature calcium dynamics and electrical coupling in recellularized dECM. In summary, decellularization of human hearts provides a biocompatible scaffold that retains 3-dimensional architecture and vascularity and that can be recellularized with parenchymal and vascular cells. dECM promotes cardiocyte gene expression in stem cells and organizes existing cardiomyocytes into nascent muscle showing electrical coupling. These findings represent a first step toward manufacturing human heart grafts or matrix components for treating cardiovascular disease.
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain; Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain; Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Sánchez
authors.affiliation: Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain; Cell Production Unit, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Fernández-Santos
authors.affiliation: Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain; Department of Cardiac Surgery, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Costanza
authors.affiliation: Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Andreu M
authors.initials: AM
authors.lastname: Climent
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Moscoso
authors.affiliation: Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Gonzalez-Nicolas
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain; Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sanz-Ruiz
authors.affiliation: Cell Production Unit, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Hugo
authors.initials: H
authors.lastname: Rodríguez
authors.affiliation: Center for Cardiovascular Repair, University of Minnesota, Minneapolis, USA.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Kren
authors.affiliation: National Transplant Organization (ONT), Spanish Ministry of Health and Consumption, Spain.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Garrido
authors.affiliation: Solid Organ Transplantation Program, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Escalante
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Bermejo
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Elizaga
authors.affiliation: Department of Pathology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Menarguez
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Yotti
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: Candelas
authors.initials: C
authors.lastname: Pérez del Villar
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain; Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Espinosa
authors.affiliation: Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: Guillem
authors.affiliation: Regenerative Medicine Research, Texas Heart Institute, Houston, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bernad
authors.affiliation: National Transplant Organization (ONT), Spanish Ministry of Health and Consumption, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Matesanz
authors.affiliation: Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain; Regenerative Medicine Research, Texas Heart Institute, Houston, USA. Electronic address: dtaylor@texasheart.org.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Taylor
authors.affiliation: Department of Cardiology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain; Bioartifical Organs Laboratory, Department of Cardiology, Instituto de Investigación Sanitaria Hospital Gregorio Marañon (IiSGM), Madrid, Spain. Electronic address: faviles@secardiologia.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Avilés
mesh_terms: D002474:Cell-Free System; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005109:Extracellular Matrix / Q000737:chemistry* / Q000648:ultrastructure; D006321:Heart / Q000254:growth & development*; D006354:Heart, Artificial; D006801:Humans; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology; D009924:Organ Culture Techniques / Q000379:methods*; D023822:Tissue Engineering / Q000295:instrumentation; D054457:Tissue Scaffolds
keywords: Cardiovascular diseases; Cells; Myocardium; Tissue