Periodic Reporting for period 2 - Mini-HEART (Human mini hearts: looking for culprits and victims in cardiac disease)
Reporting period: 2023-03-01 to 2024-08-31
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.
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”.
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”.
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.