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Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells

Disheet Shah1, Laura Virtanen2,3, Chandra Prajapati4

  • 1BioMediTech, Faculty of Medicine and Health Technology; Tampere University, 33520 Tampere, Finland. Disheet.shah@tuni.fi.

Cells
|June 19, 2019
PubMed

Insights

This study models dilated cardiomyopathy (DCM) using patient-derived stem cells. Mutant heart cells show stress sensitivity and arrhythmias, providing insights into disease mechanisms.

Area of Science:

  • Cardiovascular Biology
  • Stem Cell Biology
  • Genetics

Background:

  • Dilated cardiomyopathy (DCM) is a major cause of heart failure and transplantation.
  • Familial DCM can result from mutations in the LMNA gene, leading to poor patient prognosis.
  • LMNA mutations affect nuclear lamina proteins lamin A and C.

Purpose of the Study:

  • To develop a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model for LMNA-related DCM.
  • To investigate the pathobiology of DCM caused by the p.S143P LMNA mutation.
  • To analyze cellular structure, function, and gene/protein expression in mutant hiPSC-CMs.

Main Methods:

  • Reprogramming skin fibroblasts from DCM patients with the p.S143P LMNA mutation into hiPSCs.
  • Differentiating hiPSCs into cardiomyocytes (CMs).
  • Assessing cellular structure, electrophysiology, Ca2+ dynamics, and stress response (hypoxia).

Main Results:

  • Mutant hiPSC-CMs exhibited normal sarcomere structure under normoxia but showed damage after hypoxia.
  • Electrophysiological evaluation revealed bradyarrhythmia and increased arrhythmias upon beta-adrenergic stimulation.
  • Mutant hiPSC-CMs displayed heightened sensitivity to hypoxia and altered calcium handling.

Conclusions:

  • The p.S143P hiPSC-CM model effectively mimics key features of LMNA-related DCM.
  • This model serves as a valuable tool for studying the cellular mechanisms driving cardiac degeneration in this disease.
  • Findings highlight the impact of LMNA mutations on cardiomyocyte structure, function, and stress response.

Keywords:
LMNALamin A/Cdilated cardiomyopathyhypoxiainduced pluripotent stem cellmicroelectrode array and calcium imaging

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