DCM-on-a-chip : Dilated cardiomyopathy disease model

Abstract

Dilated cardiomyopathy is a familial heart disease, causing defects of varying severity in patients of different ages. This condition is is considered as one of the most important causes of sudden cardiac death. Several proteins and their mutations have been linked to the development of dilated cardiomyopathy, but lamins A and C, and their gene LMNA is the most common in Finnish population. Lamins A and C are responsible for the formation of nuclear lamina, a meshowrk structure, beneath the nuclear membrane. This structure is important in mechanotransduction processes as well as in gene regulation. As the collection of adult human cardiomyocytes is a burden for the patient and the existing animal models are not accurate enough, there is a great need for human based models to better understand complex disease, and to reach new therapeutic possibilities. In this work, human induced pluripotent stem cells are utilized to establish a cell sheet of cardiomyocytes which electrical functioning could be studied with microelectrode array technology. One control cell line (UTA.11311.EURCC) and two patient cell lines (UTA.12619.LMNA and UTA.12401.LMNA) with different mutations were used. Cells were measured on microelectrode arrays while exposing them to hypoxic stress to study the electrophysiological functioning of the cells and their response to hypoxic stress. In addition, immunocytochemistry was performed to confirm the successful differentiation of induced pluripotent stem cells into cardiomyocytes. Based on the microelectrode array data, no increased decrease in their functionality was noticed due to hypoxic stress, but the altered depolarization times and depolarization amplitudes were present right from the beginning of the measurement before the hypoxic stress was applied. These results suggested impaired functioning of the sodium channels due to the LMNA mutation that could be affecting the disease phenotype.