Human mini hearts: looking for culprits and victims in cardiac disease

Informations projet

Mini-HEART

N° de convention de subvention: 101001746

DOI

10.3030/101001746

Date de signature de la CE 23 Juillet 2021

Date de début 1 Septembre 2021

Date de fin 28 Février 2027

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 000 000,00

Contribution de l’UE

€ 2 000 000,00

Coordonné par

UNIVERSITA DEGLI STUDI DI PADOVA
Italy

Periodic Reporting for period 2 - Mini-HEART (Human mini hearts: looking for culprits and victims in cardiac disease)

Période du rapport: 2023-03-01 au 2024-08-31

Résumé du contexte et des objectifs généraux du projet

Cardiac disease is the leading cause of cell death globally, according to the World Health Organization. However, predicting cardiac arrhythmia and cardiac failure, understanding the pathological mechanisms underlying onset and progress, and devising new treatments for cardiac diseases remain challenging. Human induced pluripotent stem cells (hiPSCs) from patients could revolutionise the way we study human disease but, unfortunately, they still fall short in recapitulating complex cardiovascular diseases. We are addressing these challenges in Mini-HEART. We are building advanced three-dimensional cardiac microtissues or “mini-hearts” using different cardiac cell types that we derive from hiPSCs. We aim to 1) Capture signs of cardiac diseases that so far have been difficult to be identified with hiPSC-based models, in particular signs appearing in early adulthood; 2) Understand which of the many cell types present in the heart are responsible for triggering the disease; 3) Test new therapeutic strategies, such as gene editing, to alleviate the disease signs. Our work will create new opportunities for designing novel biomedical tools to capture cardiac disease traits in the laboratory and develop new therapeutic approaches for heart disease.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Using our three-dimensional human “mini-hearts” we have been able to capture in the laboratory the arrhythmic behaviour of cardiomyocytes from patients with different cardiac diseases affecting the heart rhythm, such as Brugada syndrome and arrhythmogenic cardiomyopathy. Previously, it proved challenging to see the phenotype with the “classical” two-dimensional cultures of cardiomyocytes from hiPSCs. We therefore succeeded in capturing postnatal and adult traits of these cardiac diseases.
Together with our collaborators, we discovered the important role of a protein contributing to the maturation of cardiomyocytes. This was one missing piece in the bigger puzzle of the different – yet not identified - factors that make heart regeneration possible.
Finally, we succeeded in correcting DNA mutations in cardiomyocytes from hiPSCs using novel and advanced gene editing strategies. In the next part of the project we will apply the same approach to the three-dimensional “mini-hearts”.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

With the Mini-Heart project we moved beyond the state of the art because we succeeded in capturing some signs of adult diseases that so far were not possible to see and to study in the laboratory. With the work that we will carry out in the next 2.5 years, we expect to increase the number of postnatal and adult cardiac diseases that we can study in the laboratory, understand the role of other cell types in the heart, such as cells of the immune system and neurons, in playing a role in the development of cardiac disorders, and deliver new tools for the genetic correction of several familial cardiac disease forms.

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