Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease.

Cell Differentiation Endothelial Cells Heart Diseases Humans Induced Pluripotent Stem Cells Myocytes, Cardiac Stromal Cells

arrhythmogenic cardiomyopathy cAMP cardiac disease model cardiac microtissue cardiomyocyte maturation cell-cell interaction cyclic AMP gap junction human-induced-pluripotent-stem-cell-derived cardiac fibroblasts human-induced-pluripotent-stem-cell-derived cardiomyocytes

Journal

Cell stem cell

ISSN: 1875-9777

Titre abrégé: Cell Stem Cell

Pays: United States

ID NLM: 101311472

Informations de publication

Date de publication:
04 06 2020

Historique:

received: 03 02 2020

revised: 05 04 2020

accepted: 01 05 2020

pubmed: 28 5 2020

medline: 28 4 2021

entrez: 28 5 2020

Statut: ppublish

Résumé

Cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) are functionally immature, but this is improved by incorporation into engineered tissues or forced contraction. Here, we showed that tri-cellular combinations of hiPSC-derived CMs, cardiac fibroblasts (CFs), and cardiac endothelial cells also enhance maturation in easily constructed, scaffold-free, three-dimensional microtissues (MTs). hiPSC-CMs in MTs with CFs showed improved sarcomeric structures with T-tubules, enhanced contractility, and mitochondrial respiration and were electrophysiologically more mature than MTs without CFs. Interactions mediating maturation included coupling between hiPSC-CMs and CFs through connexin 43 (CX43) gap junctions and increased intracellular cyclic AMP (cAMP). Scaled production of thousands of hiPSC-MTs was highly reproducible across lines and differentiated cell batches. MTs containing healthy-control hiPSC-CMs but hiPSC-CFs from patients with arrhythmogenic cardiomyopathy strikingly recapitulated features of the disease. Our MT model is thus a simple and versatile platform for modeling multicellular cardiac diseases that will facilitate industry and academic engagement in high-throughput molecular screening.

Identifiants

DOI: 10.1016/j.stem.2020.05.004 PMID: 32459996 PMC: PMC7284308

pubmed: 32459996

pii: S1934-5909(20)30202-2

doi: 10.1016/j.stem.2020.05.004

pmc: PMC7284308

pii:

doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

862-879.e11

Commentaires et corrections

Type : CommentIn

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Interests C.L.M. is co-founder of Ncardia bv.

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