Ischemic Heart Disease, Stem Cell Biology, Molecular/Cellular Therapeutics, and Bioengineering
The Woo lab uses cardiac surgery and coronary ligation as a model to study ischemic cardiomyopathy and stem cell biology, as well as to test novel molecular and cellular therapeutics. In vivo models include small animal (rodents), large animal (sheep and pigs), as well as human clinical trials. The lab principally focuses on developing therapies that prevent ischemic cardiomyopathy through angiogenesis, myocardial regeneration, or development of engineered symbiotic relationships.
Myocardial ischemia, infarction, and heart failure constitute a disease spectrum that is rapidly becoming one of the foremost global health challenges. Current therapies focus upon pharmacologic optimization and macrorevascularization via coronary stenting and coronary artery bypass grafting. Yet, these contemporary treatment strategies fail to address the significant microvascular malperfusion that accompanies myocardial infarction. Numerous studies have demonstrated a survival advantage in patients with robust collateralization. Along similar lines, in a region subtended by an occluded coronary artery, myocardial contractility can be completely preserved, likely supplied instead through vital collateral microvasculature. Thus, endogenous revascularization and repair mechanisms exist and the benefits are clear; but the native potency is frequently inadequate. This represents an excellent therapeutic target: the manipulation and augmentation of endogenous revascularization around the time of infarction may rescue peri-infarct myocardium, thereby restoring metabolic and mechanical properties and averting detrimental remodeling.
We have studied the primary effectors of endogenous microrevascularization, endothelial progenitor stem cells (EPC) and their potent chemokine stromal cell derived factor 1-alpha (SDF). Using SDF, we were able to significantly augment microvascular angiogenesis and improve cardiomyocyte perfusion, local tissue biomechanical properties, ventricular geometry, and cardiac function after myocardial ischemic injury. Via computational protein chemistry, we then designed and synthesized a supra-efficient engineered SDF analog (ESA). We also constructed a tissue engineered EPC extracellular-matrix simulating scaffold as an EPC delivery system that enhanced cell retention and survival. Elements of our work were upscaled into a preclinical sheep model and also translated into a human clinical trial of EPC delivery during CABG.
We are developing myocardial regeneration strategies to repair the heart following an ischemic insult by stimulating resident cardiomyocytes to re-enter the cell cycle. Specifically, we have created an engineered hydrogel system encapsulating neuregulin-β1 (NRG), which can provide targeted and sustained release of this growth factor to the area of myocardium surrounding an infarct. NRG functions via the ErbB receptor pathway to induce cardiomyocyte regeneration. We have demonstrated this in isolated cardiomyocytes, as well as in a mouse model of ischemic cardiomyopathy. In the mouse model, a significant enhancement in ventricular function was observed after targeted delivery of the hydrogel encapsulated NRG around an infarct. Currently, this project is progressing through a pre-clinical large animal phase.