Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy

Sean L Kim; Michael A Trembley; Keel Yong Lee; Suji Choi; Luke A MacQueen; John F Zimmerman; Lousanne H C de Wit; Kevin Shani; Douglas E Henze; Daniel J Drennan; Shaila A Saifee; Li Jun Loh; Xujie Liu; Kevin Kit Parker; William T Pu

doi:10.1016/j.stemcr.2023.07.005

Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy

Stem Cell Reports. 2023 Sep 12;18(9):1811-1826. doi: 10.1016/j.stemcr.2023.07.005. Epub 2023 Aug 17.

Authors

Affiliations

¹ Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA; Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA.
² Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA.
³ Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA; Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea.
⁴ Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA.
⁵ Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA; Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address: kkparker@g.harvard.edu.
⁶ Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: william.pu@cardio.chboston.edu.

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in Plakophilin-2 (PKP2), a desmosome component within specialized cardiac cell junctions, cause the majority of ACM cases. However, the molecular mechanisms by which PKP2 variants induce disease phenotypes remain unclear. Here we built bioengineered platforms using genetically modified human induced pluripotent stem cell-derived cardiomyocytes to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro. Heterozygosity for truncating variant PKP2^R413X reduced Wnt/β-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and reduced calcium wave velocity in engineered tissues. These abnormalities were ameliorated by SB216763, which activated Wnt/β-catenin signaling, improved cytoskeletal organization, restored cell junction integrity in cell pairs, and improved calcium wave velocity in engineered tissues. Together, these findings highlight the therapeutic potential of modulating Wnt/β-catenin signaling in a human model of ACM.

Keywords: arrhythmogenic cardiomyopathy; cardiac tissue engineering; cell pairs; disease modeling; human induced pluripotent stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Calcium Signaling
Humans
Induced Pluripotent Stem Cells*
Intercellular Junctions
Myocytes, Cardiac
Plakophilins / genetics
beta Catenin / genetics

Substances

beta Catenin
Plakophilins

Abstract

Publication types

MeSH terms

Substances

Grants and funding