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HEIndividual fellowship2023–2025

ACCURACY · Human cardiac microtissues for studying lamin cardiomyopathy

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-06-01 → 2025-05-31
EU contribution
€172,750
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Human cardiac microtissues for studying lamin cardiomyopathy

Heart disease places a significant burden on multiple aspects of society—primarily by shortening the lifespan of those affected, increasing healthcare costs, and reducing the quality of life for both patients and their caregivers. Familial dilated cardiomyopathy is a particular form of heart disease that is genetically driven.The ACCURACY project was focused on the study of pathological variants of the LMNA gene, which encodes for the Lamin AC protein, involved in maintaining the integrity of the nucleus. Within this project, a human model that mimics dilated cardiomyopathy traits was generated in the laboratory starting from pluripotent stem cells. It was possible to generate different cell types of the heart, including cardiomyocytes (the cells that develop the force of contraction), cells of the vessels, and the supporting cells. The study highlighted that all of the different heart cells were affected by the disease. By aggregating the distinct cardiac cell types, a three-dimensional model of cardiomyopathy was generated. Here, the pathological features previously observed in cardiomyocytes alone were enhanced by their culture in a three-dimensional environment. These results were important for better understanding the disease mechanisms and the link between the genetic defect and the abnormal cardiac function. By providing a novel model and shedding light into the cellular and molecular mechanisms of dilated cardiomyopathy caused by mutations in Lamin AC, the ACCURACY project can contribute to defining new ideas for developing new treatments. Ultimately this could result in better disease management for patients and their families.

Data: CORDIS, © European Union

Project objective

Lamin A/C cardiomyopathy (LMNA-CM) is a rare genetic disorder caused by mutations in the nuclear lamin gene LMNA. Affected patients typically exhibit dilated cardiomyopathy and reduced life expectancy, due to sudden cardiac death or accelerated functional decay requiring the heart transplant. Intriguingly, carriers of the same LMNA mutation show a wide spectrum of genotype-phenotype discrepancy, however a clear mechanistical understanding remains elusive. Recently, the host laboratory has developed an innovative multicellular three-dimensional (3D) human induced pluripotent stem cells (hiPSC)-cardiac microtissue (MT) model where hiPSC-derived cardiomyocytes display post-natal maturation allowing more faithful investigation of normal and pathological cardiac physiology. I will leverage this model and combine it with my strong background in molecular and cellular cardiology to advance the understanding of LMNA-related pathologies. Specifically, I will use patient-derived hiPSC from two family members with a severe and less severe form of LMNA-CM and their isogenic controls to generate 3D MT models. Next, I plan to 1) characterize structural and functional properties and the transcriptome profile of multicellular LMNA MT models and their controls, 2) investigate cell-cell (cardiomyocytes, endothelial cells, cardiac fibroblasts and macrophages) interactions relevant to the disease development and progression, and 3) correct the identified molecular targets by pharmacological treatment or by CRISPR-mediated gene editing. The scientific, industrial and economic community will profit from this project twofold. First, I will establish a cost-effective model that provides better understanding of LMNA-CM pathogenesis, avoids cross-species variability and reduces the need for animal research and second, I will test the implementation of potential treatment options with the ambition to achieve a step forward in developing personalized therapeutic approach for the end users.

Original text from CORDIS.

Participants

  • UNIVERSITA DEGLI STUDI DI PADOVA · PadovaCoordinatorItaly

Links

Data: CORDIS, © European Union