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Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for TNNT2 Δ160E-Induced Cardiomyopathy.

Takumi Kondo1, Shuichiro Higo2, Mikio Shiba1

  • 1Department of Cardiovascular Medicine (T.K., M.S., S.K., T.T., H.I., S. Okuno, S.Ogawa, Y.K., J.-K.L., S. Hikoso, Y.S.).

Circulation. Genomic and Precision Medicine
|July 21, 2022
PubMed
Summary

The TNNT2 Δ160E mutation causes hypertrophic cardiomyopathy by impairing calcium handling in heart cells. This study developed a human iPSC-CM model to investigate the mutation

Keywords:
cardiomyopathy, hypertrophicheart failuremutationphenotypeprognosistroponin

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Area of Science:

  • Cardiovascular Biology
  • Genetics
  • Stem Cell Biology

Background:

  • The TNNT2 gene encodes troponin T, a critical component of cardiac muscle.
  • A rare Δ160E mutation in TNNT2 is linked to hypertrophic cardiomyopathy (HCM) and poor prognosis.
  • A human model is needed to study the TNNT2 Δ160E mutation's effects and develop therapies.

Purpose of the Study:

  • To investigate the pathological phenotype caused by the TNNT2 Δ160E mutation.
  • To generate and characterize isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) modeling the mutation.
  • To establish a human model for therapeutic development in HCM.

Main Methods:

  • Generated isogenic iPSC lines with heterozygous, homozygous corrected, and homozygous introduced TNNT2 Δ160E mutations using genome editing.
  • Differentiated iPSC lines into cardiomyocytes (iPSC-CMs) for phenotypic analysis.
  • Utilized calcium imaging, high-content imaging, and biochemical assays to assess cellular function and signaling pathways.

Main Results:

  • Heterozygous and homozygous Δ160E iPSC-CMs exhibited prolonged calcium decay, impaired relaxation, and hypertrophy.
  • Phenotypes were dose-dependent, with homozygous mutation showing exacerbated effects.
  • The mutation promoted hypertrophic signaling via NFATc1 nuclear translocation and altered CaMKIIδ/phospholamban phosphorylation.
  • A calcium-sensitizing compound, epigallocatechin-3-gallate, ameliorated the observed calcium handling and relaxation defects.

Conclusions:

  • Isogenic iPSC-CMs accurately recapitulate the TNNT2 Δ160E mutation's pathological effects on calcium handling and signaling.
  • This iPSC-CM model provides a valuable platform for understanding HCM pathogenesis and testing therapeutic interventions.
  • The findings highlight the potential of targeting calcium dysregulation for treating TNNT2-associated hypertrophic cardiomyopathy.