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Cardiac Fibrotic Remodeling on a Chip with Dynamic Mechanical Stimulation.

ABSTRACT: Cardiac tissue is characterized by being dynamic and contractile, imparting the important role of biomechanical cues in the regulation of normal physiological activity or pathological remodeling. However, the dynamic mechanical tension ability also varies due to extracellular matrix remodeling in fibrosis, accompanied with the phenotypic transition from cardiac fibroblasts (CFs) to myofibroblasts. It is hypothesized that the dynamic mechanical tension ability regulates cardiac phenotypic transition within fibrosis in a strain-mediated manner. In this study, a microdevice that is able to simultaneously and accurately mimic the biomechanical properties of the cardiac physiological and pathological microenvironment is developed. The microdevice can apply cyclic compressions with gradient magnitudes (5-20%) and tunable frequency onto gelatin methacryloyl (GelMA) hydrogels laden with CFs, and also enables the integration of cytokines. The strain-response correlations between mechanical compression and CFs spreading, and proliferation and fibrotic phenotype remolding, are investigated. Results reveal that mechanical compression plays a crucial role in the CFs phenotypic transition, depending on the strain of mechanical load and myofibroblast maturity of CFs encapsulated in GelMA hydrogels. The results provide evidence regarding the strain-response correlation of mechanical stimulation in CFs phenotypic remodeling, which can be used to develop new preventive or therapeutic strategies for cardiac fibrosis.

SUBMITTER: Kong M

PROVIDER: S-EPMC6546425 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Cardiac Fibrotic Remodeling on a Chip with Dynamic Mechanical Stimulation.

Kong Ming M Lee Junmin J Yazdi Iman K IK Miri Amir K AK Lin Yi-Dong YD Seo Jungmok J Zhang Yu Shrike YS Khademhosseini Ali A Shin Su Ryon SR

Advanced healthcare materials 20190104 3

Cardiac tissue is characterized by being dynamic and contractile, imparting the important role of biomechanical cues in the regulation of normal physiological activity or pathological remodeling. However, the dynamic mechanical tension ability also varies due to extracellular matrix remodeling in fibrosis, accompanied with the phenotypic transition from cardiac fibroblasts (CFs) to myofibroblasts. It is hypothesized that the dynamic mechanical tension ability regulates cardiac phenotypic transit ...[more]

PMID: 30609312

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Project description:Myocardial fibrosis is a major determinant of clinical outcomes in heart failure (HF) patients. It is characterized by the emergence of myofibroblasts and early activation of pro-fibrotic signaling pathways before adverse ventricular remodeling and progression of HF. Boron has been reported in recent years to augment the innate immune system and cell proliferation, which play an important role in the repair and regeneration of the injured tissue. Currently, the effect of boron on cardiac contractility and remodeling is unknown. In this study, we investigated, for the first time, the effect of boron supplementation on cardiac function, myocardial fibrosis, apoptosis and regeneration in a rat model myocardial infarction (MI)-induced HF. MI was induced in animals and borax, a sodium salt of boron, was administered for 7 days, p.o., 21 days post-injury at a dose level of 4 mg/kg body weight. Transthoracic echocardiographic analysis showed a significant improvement in systolic and diastolic functions with boron treatment compared to saline control. In addition, boron administration showed a marked reduction in myocardial fibrosis and apoptosis in the injured hearts, highlighting a protective effect of boron in the ischemic heart. Interestingly, we observed a tenfold increase of nuclei in thin myocardial sections stained positive for the cell cycle marker Ki67 in the MI boron-treated rats compared to saline, indicative of increased cardiomyocyte cell cycle activity in MI hearts, highlighting its potential role in regeneration post-injury. We similarly observed increased Ki67 and BrdU staining in cultured fresh neonatal rat ventricular cardiomyocytes. Collectively, the results show that boron positively impacted MI-induced HF and attenuated cardiac fibrosis and apoptosis, two prominent features of HF. Importantly, boron has the potential to induce cardiomyocyte cell cycle entry and potentially cardiac tissue regeneration after injury. Boron might be beneficial as a supplement in MI and may be a good candidate substance for anti-fibrosis approach.

Project description:Cells in the cardiovascular system are constantly exposed to complex mechanical stimulation due to the pulsatile nature of blood flow and the haemodynamic forces that are key to the regulation of vascular development, remodeling and pathophysiology. Mechanical stretch can also modulate the differentiation of stem cells toward vascular cell lineages (i.e., vascular smooth muscle cells), and represent a critical factor in vascular tissue engineering. Here we report on the development of a microchip platform that can emulate several key aspects of the vascular mechanical environment, such as cyclic stimulation and circumferential strain. This chip consists of an array of microfluidic channels with widths ranging from 20 to 500 micrometers. These channels are covered by suspended deformable membranes, on which cells are cultured and stimulated by cyclic circumferential strain of up to 20% via hydrodynamic actuation of the fluid in the microfluidic channels, thereby mimicking the biomechanical conditions of small blood vessels. We show that human mesenchymal stem cells (MSCs) can be cultured and continuously stimulated by cyclic stretch over a period of 7 days with no evidence of device fatigue or performance degradation. We observed localization and alignment of MSCs when mechanical stretch is larger than 10%, indicating the importance of mechanical stimulation in modulating cellular behavior. We further demonstrated simultaneous detection of proteins in multiple signaling pathways, including SMAD1/SMAD2 and canonical Wnt/?-catenin. This microchip represents a generic and versatile platform for high-throughput and rapid screening of cellular responses, including signal transduction cascades, in response to mechanical cues. The system emulates the physiological conditions of blood vessels and other tissues that are subject to cyclic strain, and may have a wide range of applications in the fields of stem cell mechanobiology, vascular tissue engineering, and other areas of regenerative medicine.

Dataset Information

Cardiac Fibrotic Remodeling on a Chip with Dynamic Mechanical Stimulation.

Publications

Cardiac Fibrotic Remodeling on a Chip with Dynamic Mechanical Stimulation.

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