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-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.
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.
Electronic supplementary material
The online version of this article (10.1186/s13036-019-0139-6) contains supplementary material, which is available to authorized users.
Depression is a serious medical illness that is one of the most prevalent psychiatric disorders. Corticosterone (CORT) increases depression-like behavior, with some effects on anxiety-like behavior. 2-Phenethylamine (PEA) is a monoamine alkaloid that acts as a central nervous system stimulant in humans. Here, we show that PEA exerts antidepressant effects by modulating the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element binding protein (CREB) signaling pathway in CORT-induced depression. To investigate the potential effects of PEA on CORT-induced depression, we first treated CORT (50 μM)-induced hippocampal neurons with 100 μM PEA for 24 h. We found that treatment with CORT altered dendritic spine architecture; however, treatment with PEA rescued dendritic spine formation via regulation of BDNF/TrkB/CREB signaling. Next, we used a mouse model of CORT-induced depression. Mice were treated with CORT (20 mg/kg) for 21 days, followed by assessments of a battery of depression-like behaviors. During the final four days of CORT exposure, the mice were treated with PEA (50 mg/kg). We found that CORT injection promoted depression-like behavior and significantly decreased BDNF and TrkB expression in the hippocampus. However, treatment with PEA significantly ameliorated the behavioral and biochemical changes induced by CORT. Our findings reveal that PEA exerts antidepressant effects by modulating the BDNF/TrkB/CREB signaling pathway in a mouse model of CORT-induced depression.
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