Related Experiment Video

Updated: Jun 10, 2025

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes

Published on: June 3, 2018

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Hypertrophic cardiomyopathy-associated mutations drive stromal activation via EGFR-mediated paracrine signaling

Jourdan K Ewoldt1, Miranda C Wang1,2,3, Micheal A McLellan1,2

  • 1Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.

Science Advances
|October 16, 2024
PubMed

Insights

This study reveals paracrine signaling from hypertrophic cardiomyopathy (HCM) variant cardiomyocytes drives fibroblast proliferation and fibrosis. Inhibiting this signaling pathway may offer a therapeutic strategy for HCM.

Area of Science:

  • Cardiovascular Biology
  • Stem Cell Biology
  • Fibrosis Research

Background:

  • Hypertrophic cardiomyopathy (HCM) involves left ventricular thickening and fibrosis, linked to sarcomere gene mutations.
  • Existing in vitro models using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) lack examination of multicellular interactions in fibrosis.

Purpose of the Study:

  • To investigate the role of cell-cell cross-talk in HCM-associated fibrosis using engineered cardiac microtissues (CMTs).
  • To identify molecular mechanisms driving fibrosis in HCM, focusing on paracrine signaling.

Main Methods:

  • Engineered cardiac microtissues (CMTs) composed of MYH7-variant hiPSC-CMs and wild-type fibroblasts.
  • Analysis of collagen deposition, tissue stiffening, contractility, and fibroblast proliferation.
  • Single-nucleus RNA sequencing and conditioned media analysis to identify paracrine signals.
  • Pharmacological inhibition of epidermal growth factor receptor tyrosine kinase.

Main Results:

  • HCM-variant hiPSC-CMs and fibroblasts in CMTs showed increased collagen deposition, tissue stiffening, and reduced contractility, dependent on fibroblast proliferation.
  • Paracrine signals from MYH7-variant cardiomyocytes were identified as mediators of fibroblast proliferation.
  • Erlotinib hydrochloride treatment attenuated stromal activation.
  • MYBPC3-variant CMTs exhibited distinct fibrotic characteristics.

Conclusions:

  • A paracrine-mediated cross-talk between cardiomyocytes and fibroblasts contributes to fibrotic changes in HCM.
  • Targeting fibroblast activation via paracrine signaling presents a potential therapeutic avenue for HCM.

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