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The heart has a dynamic mechanical environment contributed by its unique cellular composition and the resultant complex tissue structure. In pathological heart tissue, both the mechanics and cell composition can change and influence each other. As a result, the interplay between the cell phenotype and mechanical stimulation needs to be considered to understand the biophysical cell interactions and organization in healthy and diseased myocardium. In this work, we hypothesized that the overall tissue organization is controlled by varying densities of cardiomyocytes and fibroblasts in the heart. In order to test this hypothesis, we utilized a combination of mechanical strain, co-cultures of different cell types, and inhibitory drugs that block intercellular junction formation. To accomplish this, an image analysis pipeline was developed to automatically measure cell type-specific organization relative to the stretch direction. The results indicated that cardiac cell type-specific densities influence the overall organization of heart tissue such that it is possible to model healthy and fibrotic heart tissue in vitro. This study provides insight into how to mimic the dynamic mechanical environment of the heart in engineered tissue as well as providing valuable information about the process of cardiac remodeling and repair in diseased hearts.
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Exploring cardiac form and function: A length-scale computational biology approach
The ability to adequately pump blood throughout the body is the result of tightly regulated feedback mechanisms that exist across many spatial scales in the heart. Diseases which impede the function at any one of the spatial scales can cause detrimental cardiac remodeling and eventual heart failure. An overarching goal of cardiac research is to use engineered heart tissue in vitro to study the physiology of diseased heart tissue, develop cell replacement therapies, and explore drug testing applications. A commonality within the field is to manipulate the flow of mechanical signals across the various spatial scales to direct self-organization and build functional tissue. Doing so requires an understanding of how chemical, electrical, and mechanical cues can be used to alter the cellular microenvironment. We discuss how mathematical models have been used in conjunction with experimental techniques to explore various structure–function relations that exist across numerous spatial scales. We highlight how a systems biology approach can be employed to recapitulate in vivo characteristics in vitro at the tissue, cell, and subcellular scales. Specific focus is placed on the interplay between experimental and theoretical approaches. Various modeling methods are showcased to demonstrate the breadth and power afforded to the systems biology approach. An overview of modeling methodologies exemplifies how the strengths of different scientific disciplines can be used to supplement and/or inspire new avenues of experimental exploration. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Cellular Models Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models KEYWORDS cardiac modeling, deterministic models, model validation
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- Award ID(s):
- 1763272
- PAR ID:
- 10146646
- Date Published:
- Journal Name:
- Wiley Interdisciplinary Reviews: Systems Biology and Medicine
- Volume:
- 12
- Issue:
- 2
- ISSN:
- 1939-5094
- Page Range / eLocation ID:
- e1470
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1002/wsbm.1470
