The work we performed was divide in several workpackages (WPs). Below I will described the achieved results so far regarding the different WPs.
WP1: we achieved the generation of 3D cardiac tissue with the use of induced pluripotent stem cells. With this model we are able to put load on the tissues which stretches the tissue. In healthy cells this resulted in better contractility, but in diseased cells (i.e. cell with mutations in the desmosome) this resulted in a strong phenotype.
WP2a/WP3: this WP is related to unraveling peripartum cardiomyopathy, as an example disease. PPCM is a a form of heart failure which occurs late during pregnancy or in the first months after delivery. We generated hiPSC derived cardiomyocytes from 2 patients with PPCM and their used their healthy relatives as a control. With the use of RNAsequencing (WP3), we found that cardiomyocytes from PPCM patients showed a dysregulated metabolic activity. Key factor involved here will be further investigated.
WP2b: this WP is related to why certain chemotherapeutics lead to cardiotoxicity in some patients, while others are resistant to develop this toxicity. We generated hiPSC derived cardiomyocytes from 3 patients with severe toxicity and will compare them to 3 patients without toxicity. These studies are now ongoing.
FINAL PERIOD
STOP-HF focused on molecular mechanisms that contribute to the development of HF. It is aimed at elucidating the current knowledge gap in molecular mechanisms related to the early pathogenesis of HF before irreversible damage occurs. In this project we used an innovative and multidisciplinary approach. By using human induced pluripotent cells (hiPSC) technology we generated patient-specific heart cells from patients with heart failure (circumventing the need for cardiac biopsies) and used next generation sequencing to identify novel pathways/targets in the pathophysiology of HF.
We achieved 3 major goals:
1) Construction of 3D dynamic engineered heart tissue
2) Uncovering of a novel disease pathway in peripartum cardiomyopathy with the use of human induced pluripotent stem cells
3) Identification of a disease mechanism in patients with a cardio-cutaneous syndrome caused by a KLHL24-gain of function mutation
The work we performed was divide in several workpackages (WPs). Below I will described the achieved results so far regarding the different WPs.
WP1: we achieved the generation of 3D cardiac tissue with the use of induced pluripotent stem cells. With this model we are able to put load on the tissues which stretches the tissue. In healthy cells this resulted in better contractility, but in diseased cells (i.e. cell with mutations in the desmosome) this resulted in a strong phenotype.
WP2a/WP3: this WP is related to unraveling peripartum cardiomyopathy, as an example disease. PPCM is a a form of heart failure which occurs late during pregnancy or in the first months after delivery. We generated hiPSC derived cardiomyocytes from 2 patients with PPCM and their used their healthy relatives as a control. With the use of RNAsequencing (WP3), we found that cardiomyocytes from PPCM patients showed a dysregulated metabolic activity. Key factor involved here will be further investigated. WP2b: this WP is related to why certain chemotherapeutics lead to cardiotoxicity in some patients, while others are resistant to develop this toxicity. We generated hiPSC derived cardiomyocytes from 3 patients with severe toxicity and compared them to 3 patients without toxicity. Several targets were identified and we are exploring the pathophysiology behind these mechanisms. One striking difference was observed in genes involved in the uptake of drugs. We are exploring with the Technology Transfer Officer whether these targets can be patented.
REF:
J Clin Invest . 2021 Jul 22;131(17):e140615. doi: 10.1172/JCI140615
Nat Rev Cardiol. 2022 Jan 11. doi: 10.1038/s41569-021-00664-8
Circulation. 2020 Dec 8;142(23):2288-2291. doi: 10.1161/CIRCULATIONAHA.119.044962.
Sci Transl Med . 2021 Jul 21;13(603):eabd1817. doi: 10.1126/scitranslmed.abd1817.
