While interstitial fibrosis plays a significant role in heart failure, our understanding of disease progression in humans is limited. To address this limitation, we have engineered a cardiacfibrosis-on-a-chip model consisting of a microfabricated device with live force measurement capabilities using co-cultured human cardiac fibroblasts and pluripotent stem cell-derived cardiomyocytes. Transforming growth factor-β was used as a trigger for fibrosis. Here, we have reproduced the classic hallmarks of fibrosis-induced heart failure including high collagen deposition, increased tissue stiffness, BNP secretion, and passive tension. Force of contraction was significantly decreased in fibrotic tissues that displayed a transcriptomic signature consistent with human cardiac fibrosis/heart failure. Treatment with an anti-fibrotic drug decreased tissue stiffness and BNP secretion, with corresponding changes in the transcriptomic signature. This model represents an accessible approach to study human heart failure in vitro, and allows for testing anti-fibrotic drugs while facilitating the real-time assessment of cardiomyocyte function.
ERCURY IS WIDESPREAD IN the environment, originating from both natural a n d a n t h r o p o g e n i c sources. [1][2][3] The general population may be exposed to 3 forms of mercury: elemental, inorganic, or organic (predominantly methyl). Elemental and inorganic mercury exposure can result from mercury spills, dental amalgams, exposure at the workplace, environmental exposure to natural weathering of mercury containing ores, and from the burning of coal and incineration of medical wastes. Methylmercury is formed through microbial action from inorganic mercury that has deposited in aquatic environments and bioaccumulates through the food chain so that concentrations are highest in large predatory fish. Exposure occurs primarily through consumption of seafood, freshwater fish, and shellfish. 1,[4][5][6] Methylmercury exposure is of particular concern because it is a wellestablished human neurotoxin and the developing fetus is most sensitive to its adverse effects. [1][2][3] Toxic effects of methylmercury exposure are known from past poisoning outbreaks, particularly those in Minamata, Niigata, and Kumomoto Prefecture, Japan, 7,8 and in Iraq. 9 Recent e p i d e m i o l o g i c a l s t u d i e s h a v e addressed neurodevelopmental effects in young children from in utero methylmercury exposure in populations in which fish or seafood is a substantial component of the diet and in which exposure levels may be comparable with those levels in high-end consumers in the United States. [10][11][12]
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