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Transcriptomic Characterization of a Human In Vitro Model of Arrhythmogenic Cardiomyopathy Under Topological and Mechanical Stimuli

  • Sebastian Martewicz
  • Camilla Luni
  • Elena Serena
  • Piero Pavan
  • Huei-Sheng Vincent Chen
  • Alessandra Rampazzo
  • Nicola Elvassore
Article
  • 81 Downloads

Abstract

Cell junctions play an important role in coordinating intercellular communication and intracellular ultrastructures, with desmosomes representing the mechanical component of such intercellular connections. Mutations to desmosomal component proteins compromise both inter- and intracellular signalling and correlate with severe diseases like arrhythmogenic cardiomyopathy (AC), with pathological phenotypes in tissues subjected to intense mechanical stimuli (skin and heart). Here, we explore the consequences of dysfunctional desmosomes in one line of induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) derived from an AC patient with a homozygous pathogenic mutation in desmosomal component protein plakophilin-2 (PKP2). We specifically aim at investigating the response to mechanical stress in an AC-pathological setting. To this aim, we aligned hiPS-CMs on stretchable patterned substrates to mimic the cardiac functional syncytium and compared transcriptomic profiles of PKP2-mutated hiPS-CMs and healthy controls. AC-CMs display altered transcription towards a pro-fibrotic gene expression program, and concurrent dysregulation of gene sets closely associated with cell-to-cell connections. By integrating the culture substrate with a macroscopic stretching setup able to accurately apply cyclic uniaxial elongation, we show how response to mechanical loads in AC-CMs deviates from the canonical mechanical-stress response observed in healthy-CMs.

Keywords

Aligned cardiomyocytes Stretch Arrhythmogenic cardiomyopathy Human pluripotent stem cell PKP2 hiPS-derived cardiomyocytes 

Notes

Acknowledgments

This work was supported by ShanghaiTech University to S.M., C.L., N.E. [Grant F-0301-15-009]; University of Padova [TRANSAC Progetto Strategico to A.R., N.E.]; Oak Foundation Award to N.E. Grant #W1095/OCAY-14-191; Regione del Veneto [Ricerca sanitaria finalizzata to N.E.]; National Institute of Health grant [RO1 HL105194 to H.-S.V.C.); and start-up funds from Krannert Institute of Cardiology and School of Medicine, Indiana University (to H.-S.V.C.). We thank SIAIS Informatic platform at ShanghaiTech University for high-performance computational facilities. We thank Dr. Alessandro Zambon from University of Padova for his assistance in lithography and microfabrication.

Conflict of interest

None declared.

Supplementary material

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Copyright information

© Biomedical Engineering Society 2018

Authors and Affiliations

  1. 1.Shanghai Institute for Advanced Immunochemical StudiesShanghaiTech UniversityShanghaiChina
  2. 2.Department of Industrial EngineeringUniversity of PadovaPaduaItaly
  3. 3.Venetian Institute of Molecular MedicinePaduaItaly
  4. 4.Centre for Mechanics of Biological MaterialsUniversity of PadovaPaduaItaly
  5. 5.Krannert Institute of CardiologyIndiana UniversityIndianapolisUSA
  6. 6.Department of BiologyUniversity of PadovaPaduaItaly
  7. 7.Stem Cells & Regenerative Medicine SectionUCL Great Ormond Street Institute of Child HealthLondonUK

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