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Dissecting hiPSC-CM pacemaker function in a cardiac organoid model.

Authors
  • Schulze, Mirja L1
  • Lemoine, Marc D2
  • Fischer, Alexander W3
  • Scherschel, Katharina4
  • David, Robert5
  • Riecken, Kristoffer6
  • Hansen, Arne1
  • Eschenhagen, Thomas1
  • Ulmer, Bärbel M7
  • 1 University Medical Center Hamburg Eppendorf, Institute of Experimental Pharmacology and Toxicology, 20246, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany. , (Germany)
  • 2 University Medical Center Hamburg Eppendorf, Institute of Experimental Pharmacology and Toxicology, 20246, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany; University Heart Center Hamburg, Department of Cardiology-Electrophysiology, Hamburg, Germany. , (Germany)
  • 3 University Medical Center Hamburg Eppendorf, Institute of Biochemistry and Molecular Cell Biology, 20246, Hamburg, Germany. , (Germany)
  • 4 German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany; University Heart Center Hamburg, Department of Cardiology-Electrophysiology, Hamburg, Germany. , (Germany)
  • 5 University Medicine Rostock, Department for Heart Surgery, Schillingallee 35, 18057, Rostock, Germany; University Rostock, Department of Life, Light & Matter, Albert-Einstein-Str. 25, 18059, Rostock, Germany. , (Germany)
  • 6 University Medical Center Hamburg Eppendorf, Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, 20246, Hamburg, Germany. , (Germany)
  • 7 University Medical Center Hamburg Eppendorf, Institute of Experimental Pharmacology and Toxicology, 20246, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Biomaterials
Publication Date
Jun 01, 2019
Volume
206
Pages
133–145
Identifiers
DOI: 10.1016/j.biomaterials.2019.03.023
PMID: 30933775
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Biological pacemakers could be a promising alternative to electronic pacemakers and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) may represent a suitable source for implantable cells. To further unravel this potential a thorough understanding of pacemaker function with regard to coupling processes both in the physiological and in the graft-host context is required. Here we developed a 2-component cardiac organoid model with a hiPSC-CM embryoid body (EB) as trigger casted into a rat engineered heart tissue (EHT) as arrhythmic beating substrate. Contractility recordings revealed that the EB controlled the beating activity of the EHT, leading to a regular hiPSC-CM-like beating pattern instead of the irregular beating typically seen in rat EHT. Connectivity was observed with action potential (AP) measurements and calcium transients transmitting from the EB directly into the rat EHT. Immunohistochemistry and genetically labeled hiPSC-CMs demonstrated that EB-derived and rat cells intermingled and formed a transitional zone. Connexin 43 expression followed the same pattern as histological and computer models have indicated for the human sinoatrial node. In conclusion, hiPSC-CM EBs function as a biological pacemaker in a 2-component cardiac organoid model, which provides the possibility to study electrophysiological and structural coupling mechanisms underlying propagation of pacemaker activity. Copyright © 2019. Published by Elsevier Ltd.

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