Mechanical Regulation of Fibroblast Migration and Collagen Remodeling in Healing Myocardial Infarcts

Each year, approximately 900,000 Americans experience a myocardial infarction. Most patients survive the initial event, making management of post-infarction healing and remodeling a high priority. After infarction, damaged myocardium is replaced by passive scar tissue, which impairs cardiac function and contributes toward adverse remodeling that leads to heart failure. Our lab has shown that the level of anisotropy of infarct scar is an important determinant of heart function. However, factors regulating infarct anisotropy are not well understood. Mechanical, structural, and chemical environmental cues have all been shown to regulate alignment of fibroblasts and collagen in vitro. A better understanding of how fibroblasts integrate these cues as they deposit and remodel extracellular matrix in a healing infarct is needed in order to develop interventions that modify infarct scar anisotropy for therapeutic benefit.

Our overall hypothesis was that collagen alignment in infarct scar tissue is primarily determined by mechanical cues that guide alignment of fibroblasts, which actively re-orient nearby collagen fibers. Our approach was to build a computational model of infarct healing and use it to test hypotheses about how the collagen fiber structure of infarct scar arises from the collective activity of individual fibroblasts sensing and responding to signals in their local environment.

We developed an agent-based model that accounted for the influence of mechanical, structural, and chemical cues on fibroblast alignment, collagen deposition, and collagen remodeling. We found that a mechanical cue was critical to reproducing the collagen alignment observed experimentally in healing infarcts. We also found that although active re-orientation of collagen fibers by fibroblasts could explain the collagen alignment observed in healing infarcts, aligned deposition of new collagen fibers by fibroblasts could also explain the experimental data. We performed parameter sensitivity analyses on the two alternative models, identified novel behaviors that each model predicted, and designed experiments that will further test the predictive capabilities of the models. In order to obtain experimental evidence in support of our modeling results, we created fibrin wounds in fibroblast-populated collagen gels, applied different mechanical restraints to the gels, and quantified the migration behavior of fibroblasts that entered the wounds. We found a strong guidance effect of anisotropic strain, indicating that mechanical cues can have strong effects on fibroblast behavior in wound-like environments. Finally, we developed a finite element model of an infarct and surrounding myocardium, and coupled the finite element model to our agent-based model, enabling the mechanical environment of the infarct to be updated in response to the structural remodeling that occurs during healing. The coupled model will be useful for further investigation of the mechanobiology of healing infarcts. Future versions could link the agent-based model to a finite element model of a whole heart, allowing the functional impact of different scar structures to be assessed in silico.

This work will aid the development of treatments that improve healing after myocardial infarction. We identified environmental factors and fibroblast behaviors that regulate anisotropy of infarct scar tissue and embedded this understanding in a computational framework that can be used to identify interventions that modify the properties of infarct scar for therapeutic benefit.