Emergence of Structure and Function in the Heart from Cell to Organ
Dr. Anna Grosberg
Assistant Professor of Biomedical Engineering
The Edwards Lifesciences Center for Advanced Cardiovascular Technology
University of California, Irvine
The quality of muscle tissue function depends on its ability to self organize on multiple scales, ranging from the centimeter arrangement of the muscle sheets to the micrometer alignment of sarcomeres and the nanometer assembly of focal adhesions. Thus far, cellular structural elements have not been considered in nano-scale focal adhesion protein models, and larger scale single cells mechanical models have not been used to test for biological hypotheses of self assembly. In this work, we approached the large problem of cardiac tissue formation by modeling myofibrillogenesis in single cells of varying shapes. We hypothesized that by including fiber length-force dependence, and mutual fiber alignment in the model, myofibrillogenesis of a single cell can be reproduced for any cell shape. Inside each modeled cell, we focused on the maturation of cytoskeletal structural elements responsible for contraction, integrin binding to the extracellular matrix, and fibrils maturing from pre-myofibrils to nascent myofibrils. The model was formulated in terms of experimentally observable coarse-grained fields. By comparing in silico and in vitro data from differently shaped cells, a stair-shaped cell and a circular cell, we were able to demonstrate the necessity of both fiber length-force dependence and mutual fiber alignment. This illustrates the importance of creating in silica models that can be used to investigate differences between native and stem-cell derived cardiomyocytes. At the same time, we have developed a "heart-on-a-chip" technology to measure cardiac tissue function at higher spatial scales. This technology can be used in combination with models of multiple cell constructs to investigate the response of muscle tissues to various environmental changes. Furthermore, we plan to integrate these models with a model of the myocardium to study whole heart function, which will ultimately impact the range of treatment procedures for heart failure patients.
Dr. Grosberg received her undergraduate education at the University of Minnesota, double majoring in Chemical and Biomedical Engineering. Her PhD work was done at the California Institute of Technology under the guidance of Professor Mory Gharib, where she created a computational model of the myocardium mechanics. She was then a postdoctoral fellow at Harvard University in Professor Kit Parker's Disease Biophysics Group, where she worked on both computational modeling of cellular self assembly and experimental tissue engineering device design. She started her faculty position in the Department of Biomedical Engineering in the beginning of the third quarter, and she is a part of the Cardiovascular Center.