Lee, Mi-Ok Jung, Kwang Bo Jo, Seong-Jae Hyun, Sung-Ae Moon, Kyoung-Sik Seo, Joung-Wook Kim, Sang-Heon Son, Mi-Young 2024-01-19T20:34:28Z 2024-01-19T20:34:28Z 2021-09-02 2019-02-13 1754-1611 https://pubs.kist.re.kr/handle/201004/120349 Background: Cardiac fibrosis is the most common pathway of many cardiac diseases. To date, there has been no suitable in vitro cardiac fibrosis model that could sufficiently mimic the complex environment of the human heart. Here, a three-dimensional (3D) cardiac sphere platform of contractile cardiac microtissue, composed of human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) and mesenchymal stem cells (MSCs), is presented to better recapitulate the human heart. Results: We hypothesized that MSCs would develop an in vitro fibrotic reaction in response to treatment with transforming growth factor-beta 1 (TGF-beta 1), a primary inducer of cardiac fibrosis. The addition of MSCs improved sarcomeric organization, electrophysiological properties, and the expression of cardiac-specific genes, suggesting their physiological relevance in the generation of human cardiac microtissue model in vitro. MSCs could also generate fibroblasts within 3D cardiac microtissues and, subsequently, these fibroblasts were transdifferentiated into myofibroblasts by the exogenous addition of TGF-beta 1. Cardiac microtissues displayed fibrotic features such as the deposition of collagen, the presence of numerous apoptotic CMs and the dissolution of mitochondrial networks. Furthermore, treatment with pro-fibrotic substances demonstrated that this model could reproduce key molecular and cellular fibrotic events. Conclusions: This highlights the potential of our 3D cardiac microtissues as a valuable tool for manifesting and evaluating the pro-fibrotic effects of various agents, thereby representing an important step forward towards an in vitro system for the prediction of drug-induced cardiac fibrosis and the study of the pathological changes in human cardiac fibrosis. English BMC MYOCARDIAL FIBROSIS OXIDATIVE STRESS SCAR FORMATION HEART FIBROBLAST DIFFERENTIATION CARDIOMYOCYTES CONTRIBUTE TISSUE CONNEXIN-43 Modelling cardiac fibrosis using three-dimensional cardiac microtissues derived from human embryonic stem cells Article 10.1186/s13036-019-0139-6 1 JOURNAL OF BIOLOGICAL ENGINEERING, v.13 JOURNAL OF BIOLOGICAL ENGINEERING 13 scie scopus 000458653200002 2-s2.0-85061538554 Biochemical Research Methods Biotechnology & Applied Microbiology Biochemistry & Molecular Biology Biotechnology & Applied Microbiology Article MYOCARDIAL FIBROSIS OXIDATIVE STRESS SCAR FORMATION HEART FIBROBLAST DIFFERENTIATION CARDIOMYOCYTES CONTRIBUTE TISSUE CONNEXIN-43 Cardiac fibrosis Cardiac sphere Cardiac microtissue Cardiomyocyte Mesenchymal stem cell