Abstract
BackgroundCardiac 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.ResultsWe hypothesized that MSCs would develop an in vitro fibrotic reaction in response to treatment with transforming growth factor-β1 (TGF-β1), 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-β1. 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.ConclusionsThis 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.
Highlights
Cardiac fibrosis is the most common pathway of many cardiac diseases
We showed the expression of the gap junctional protein Connexin 43 (Cx43), which plays an important role in the electrical coupling of myocardium [25], in the region of cell–cell interactions (Fig. 1e)
These results showed that CMs differentiated from human embryonic stem cell (hESC) were interconnected via Cx43-mediated gap junctions, which have a similar structure to the Cx43 gap junction plaque in the intercalated disc of cardiac muscle [26]
Summary
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. 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. The exploration of the pathogenesis and therapy development for cardiac fibrosis is hampered by the lack of appropriate experimental models that fully recapitulate human cardiac fibrosis. Most are composed of cardiac cells derived from neonatal mouse and rat hearts and have less relevance to human pathophysiology. Most current models of cardiac tissue contain only cardiomyocytes (CMs) and lack other key cell types found in the human heart [13]. There is a need for an in vitro human cardiac fibrosis model that possesses the physiologically relevant cell combination and can mimic the three-dimensional (3D) nature of native cardiac tissue
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