SiGNATURE · Selection of human iPSC-derived cardiomyocytes by sinGle cell geNe expression and pAtch clamp for a maTUre caRdiac modEl
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2020-02-01 → 2022-01-31
- Финансиране от ЕС
- 187 572 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Сърдечните клетки, създадени от стволови клетки на пациенти, се анализират, за да станат по-зрели и подобни на тези при възрастните. Това помага за по-точното разбиране на генетичните нарушения в сърцето и по-сигурното тестване на лекарства.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Selection of human iPSC-derived cardiomyocytes by sinGle cell geNe expression and pAtch clamp for a maTUre caRdiac modEl
Heart disease is a burden for the European population, as cardiovascular disease is the most common cause of death Europe and the number of people suffering from heart rhythm abnormalities (cardiac arrhythmia) is increasing. The mechanisms of arrhythmias are in some cases poorly understood, because of the lack of proper models able to accurately reproduce the human heart in a more simplified environment. Animal models have been and still are widely used to study genetic mutations leading to arrhythmia, but their differences with the human species impeded a precise reproduction of patients’ diseases. Moreover, reducing the use of animal testing for ethical reasons is one of the objectives of EU. In the last years efforts to find an alternative model for heart disease have directed the attention to human induced pluripotent stem cells (hiPSCs). These cells can be derived by reverting to the stem cell state a patient’s cells, therefore carry the same genes and mutations. They can then generate virtually unlimited amounts of human cardiomyocytes, the heart contracting cells. The use of hiPSC-derived cardiomyocytes (hiPSC-CMs) has indeed provided many insights on genetic mutations associated with heart disease. However, current technology for cardiac differentiation from stem cells is not yet producing cardiomyocytes mature enough to resemble adult heart cells for functionality and gene expression. This is particularly relevant when using the hiPSC-CMs to test drugs for cardiopathic patients who are most commonly adults: their responses may not correspond. Moreover, genetic heart diseases due to mutations in genes not expressed in immature hiPSC-CMs cannot currently be studied. In this context, SiGNATURE project aimed to improve the human cardiac model, by producing more mature and thus reliable hiPSC-CMs. The approach was to promote maturation by better mimicking the heart, which has a three-dimensional (3D) structure and is composed by different cell types, the main being CMs, fibroblasts and vascular cells. The goal was to produce a 3D multicellular culture system as simple as possible and with contained production costs, to be usable by many researchers in both academic and industrial laboratories. Moreover, the system should allow analysis at the single cell level, to investigate the precise mechanisms underlying genetic heart diseases. Combining analysis of specific gene expression and single cardiomyocyte electrical activity, the project aims at demonstrating the utility of this 3D maturation system by revealing the effects of mutations masked in immature hiPSC-CMs, providing a more consistent model to test drugs.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The incidence of cardiac arrhythmias in Europe is increasing because of aging and unexpected side effects of drugs, such as chemotherapeutics. To understand mechanisms underlying these conditions requires reliable preferably human models. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are presently good candidates since they share the genome of the individual from whom they are derived and can thus recapitulate genetic, ethnic and gender contributions to the cardiac disease phenotypes. However, their immature state and high inter- and intra-line variability is limiting their value as preclinical models. In the proposed project, I will address these issues through an interdisciplinary approach combining a unique 3D culture maturation system developed in my host lab with my expertise in electrophysiology. I will characterize gene expression and electrical properties of single cardiomyocytes simultaneously with view to directly correlating genes with function and identify molecular markers associated with the functionally mature cardiac phenotype. Two genetic cardiac diseases (one caused by an imprinted gene, the other by a postnatally expressed splice variant) for which the host already has hiPSC lines, will be used as proof of concept that hiPSC-CM maturation in this system is sufficient (i) to reveal disease phenotypes not evident in conventional culture and (ii) to identify molecular markers suitable for selecting mature hiPSC-CMs for drug testing. Overall, this project will provide the first functionally-relevant gene signature of (mature) hiPSC-CMs, and thus be an important advance in modelling all cardiomyocyte autonomous cardiac diseases more precisely for (personalized) drug screening. The outcome will be available to academic and private researchers to enhance rates of drug discovery and safety, and promote hiPSC-CMs as validated adult cardiac models to replace, at least in part, the use of animal models.
Оригинален текст от CORDIS (на английски).
Участници
- ACADEMISCH ZIEKENHUIS LEIDEN · LeidenКоординаторНидерландия
Връзки
Данни: CORDIS, © Европейски съюз