Overview
Myocardial infarctions (heart attacks) are the number one cause of death in the industrialized world. Infarcts occur when a coronary artery becomes obstructed, resulting in the rapid death of myocardium from ischemia (deficiency of blood flow). The heart has no significant intrinsic regenerative ability. As a result, infarcts heal by scar formation, and many patients suffer from heart failure after an infarct. Our group is interested in the biology of myocardial infarction, both in defining the molecular mechanisms that underlie the heart’s normal wound healing processes and in developing molecular and cell-based approaches to improve infarct repair. We are a multidisciplinary group, doing basic work in molecular biology and regulation of gene expression, cell biology, tissue engineering, mouse models of disease, and analyses of human tissues. The following serves to highlight some of the work underway in the lab.

Stem Cell Studies
Our lab is working with both adult and pluripotent (embryonic and iPSC) stem cells, with an aim to develop cellular approaches to regenerate the heart. Our work in adult stem cells is focused on creating transgenic/knock-in mice to track progenitor cells in the heart. We will use genetic pulse-chase techniques to mark candidate progenitor populations and then follow their appearance into other compartments of the heart such as muscle cells or blood vessels. We are working with mesenchymal stem cells to enhance survival of transplanted cardiomyocytes via paracrine signaling pathways. Pluripotent stem cell studies are focused on molecular pathways involved in cardiovascular differentiation, including the use of high throughput sequencing to understand chromatin remodeling and transcription factor binding. We recently identified key roles for signaling through Wnt and VEGF pathways in determining cardiac, smooth muscle and endothelial fate. We are also using these early cells to repair the infarcted heart via cell transplantation and have shown that stem cell-derived human myocardium prevents development of heart failure after experimental infarction. Recently we have succeeded in partially regenerating the hearts of non-human primates, and we hope to translate these studies to first-in-human trials of heart repair in several years.

Tissue Engineering
Tissue engineering is a new discipline that combines the worlds of cell biology, materials science and quantitative approaches to mathematical modeling and analyses typical of engineering. Our goals are threefold: 1) to create a ”patch” of contractile tissue ex vivo and implant this onto an infarcted heart for cardiac repair;  2) to understand the rules of tissue assembly, growth and development to make myocardium that is useful for drug screening or disease modeling; and 3) to use engineered heart tissues to model genetically based human heart muscle diseases.  Current approaches involve seeding cells onto synthetic, biodegradable scaffolds and utilizing a ”cells in gels” approach, where cells are seeded into hydrophilic gels containing microencapsulated growth factors and cytokines for timed release.

Human Disease Modeling

We are using human induced pluripotent stem cells (hiPSCs) obtained from patients with childhood- and adult-onset cardiomyopathies to study these genetically based diseases in vitro. We have developed single-cell and engineered heart tissue assays to assess contractile function and electrical function. A major goal is to promote the in vitro maturation of human cardiomyocytes such that they better reflect the physiology of the postnatal heart.