2. Academic Validation
  3. Phenotype specific nuclear lamina remodeling in hiPSC derived cardiomyocytes bearing TNNT2 sarcomeric variants

Phenotype specific nuclear lamina remodeling in hiPSC derived cardiomyocytes bearing TNNT2 sarcomeric variants

  • iScience. 2025 Oct 30;28(12):113901. doi: 10.1016/j.isci.2025.113901.
Isabella Leite Coscarella 1 2,  Olalekan H Usman 1,  Lili Wang 3,  Maicon Landim-Vieira 1,  Lillian Wirstiuk 1,  Amber N Brown 4,  Diego A R Zorio 4,  Brian K Washburn 4,  Cynthia Vied 5,  Bjorn C Knollmann 3,  Christopher Solís 6,  Vitold E Galkin 7,  P Bryant Chase 4,  J Travis Hinson 8 9,  Jerome Irianto 1,  Jose Renato Pinto 1
Affiliations

Affiliations

  • 1 Biomedical Sciences, Florida State University, Tallahassee, FL, USA.
  • 2 School of Medicine, Department of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
  • 3 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 4 Biological Science, Florida State University, Tallahassee, FL, USA.
  • 5 Translational Science Laboratory, Florida State University, Tallahassee, FL, USA.
  • 6 Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, FL, USA.
  • 7 Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA, USA.
  • 8 The Jackson Laboratory, Farmington, CT, USA.
  • 9 Cardiology Center, University of Connecticut Health Center, Farmington, CT, USA.
PMID: 41321620 DOI: 10.1016/j.isci.2025.113901
Abstract

Cardiomyocytes endure physical stress from the myocardium environment while generating their own mechanical strains. The force generated by sarcomeres is transmitted both longitudinally to adjacent sarcomeres and laterally to the Cytoskeleton via intermediate filaments. This mechanical stimulus impacts Other organelles, including the nucleus, thus playing a vital role in sensing and signaling nuclear adaptations. However, there is limited understanding of how changes in cardiac contractility affect nuclear mechanics. Here, we sought to investigate the effects of hyper- and hypo-contractility in nuclei of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing TNNT2 pathogenic variants associated with hypertrophic (HCM) or dilated (DCM) cardiomyopathies. Transcriptomics analyses of these variant bearing hiPSC-CMs confirmed that differential gene expression occurs and is associated with maladaptive and compensatory responses in HCM and DCM. Our findings show a cause-and-effect link between impaired contractility and nuclear lamina remodeling in cardiomyopathic phenotypes. Disease-induced dysfunctional contractile transients alter the expression of nucleoskeleton protein lamin A/C, influencing nuclear stiffness. These changes in stiffness were rescued by treatment with Myosin modulators Mavacamten or Omecamtiv Mecarbil. This study shows that nuclear mechanics is influenced by the interaction between the sarcomere and the cytoskeletal network. Exploring the relationship between contractile dysfunction and nuclear lamina remodeling may reveal new therapeutic targets for cardiomyopathies.

Keywords

Biological sciences; Cell biology; Natural sciences; Stem cells research.

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