PhD Scientific Days 2025

Poster Session II. - U: Cardiovascular Medicine and Research

Stem Cell-derived Tissue Engineering Platforms for investigating Lamin A/C-associated Dilated Cardiomyopathy

Name of the presenter

Maczelka Hédi Nóra

Institute/workplace of the presenter

Heart and Vascular Center, Semmelweis University

Authors

Hédi Nóra Maczelka¹, Dr. Barbara Orsolits², Lilla Jázmin Bakos², Ildikó Mária Ványi², Dr. Márton Sághi³, Dr. Béla Merkely², Dr. Ágota Apáti⁴, Dr. Gábor Földes²

1: Doctoral School of Semmelweis University, Budapest, Hungary
2: Heart and Vascular Center, Semmelweis University, Budapest, Hungary
3: Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
4: Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary

Text of the abstract

Introduction
Dilated cardiomyopathy (DCM) linked to Lamin A/C gene (LMNA) mutations is a severe cardiac disorder marked by poor prognosis and high mortality. As endothelial cells (ECs) serve as critical mediators between the bloodstream and cardiac tissue, their dysfunction caused by LMNA mutations may contribute significantly to DCM pathogenesis. However, the specific endothelial phenotype associated with LMNA-related DCM remains poorly understood.
Aims
This study aims to investigate the interplay between ECs and the extracellular matrix (ECM) in LMNA-related DCM using a human induced pluripotent stem cell (hiPSC) model.
Methods
Heart tissues from healthy donors (N=7) and DCM patients (N=10), collected through the Transplantation Biobank of the Heart and Vascular Centre at Semmelweis University, were analysed following LMNA mutation identification via whole exome sequencing. Histological and immunohistological quantification, furthermore LC-MS/MS were performed on the cardiac samples.
Results
Histological analysis of DCM samples revealed nuclear and cellular hypertrophy of cardiomyocytes, increased pericellular fibrosis, and capillary rarefaction. Subsequent decellularisation and quantitative ECM protein analysis indicated elevated Collagen IV and Fibronectin levels in DCM-derived matrices. Proteomic profiling identified 15 upregulated and 3 downregulated proteins (p<0.05) in DCM ECM compared to the control group.
The previously decellularised extracellular matrices were seeded with healthy and LMNA-mutant hiPSC-derived endothelial cells. The cells proliferated and survived long-term culture, maintained an endothelial phenotype, and showed signs of functional maturation.
Conclusions
This stem cell-derived DCM model enables the detailed investigation of cell-matrix dynamics and highlights potential mechanisms underlying endothelial dysfunction in LMNA-related DCM. Understanding these interactions may help the development of targeted therapies for this rare and fatal cardiomyopathy in the future.
Funding
This study was funded by RRF-2.3.1-21-2022-00003, TKP2021-EGA-23, and OTKA K146125.