Our lab translates novel molecular and cellular therapeutics for the prevention of heart failure. With experience in cellular biology, tissue engineering, radiology, and surgery, we test potential therapies in vitro, in vivo in small and large animals, and ultimately in humans. We are currently the only lab on Stanford’s campus that performs cardiovascular surgery in a preclinical ovine model.
- Understanding Endogenous Mechanisms of Angiogenesis
- Angiogenesis to Prevent Heart Failure
- Myocardial Regeneration
- Tissue Engineering to Limit Ventricular Remodeling
- Circumventing Ischemia with Photosynthesis
- Clinical Trials
- Testing Cardiovascular Therapies in Small and Large Animals
- Human Tissue Cardiovascular Biorepository
SDF signaling in endothelial progenitor cell (EPC) mobilization has been studied, however questions remain regarding the precise temporal and spatial selectivity and potency of SDF on EPC mediated neovascularization. We are currently elucidating mechanistic insight by studying specific SDF-EPC relationships via a sequential series of loss of function/gain of function experiments utilizing genetically engineered mice. Also undefined is the exact role and fate of the other main effector in this axis, the EPC. Its paracrine role is reasonably established, whereas, its fate in microvasculature composition is unknown. In fact, the identity of EPCs remains debated throughout the literature. With the use of cellular labeling, bone marrow and stem cell transplantation, we are currently in the process of tracking EPC positional, survival, and differentiation fate. A better understanding of the endogenous mechanisms of angiogenesis will greatly contribute to our understanding of the current limitations of angiogenic chemokine and stem cell therapeutics.
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) (Hiesinger et al. Circulation 2011). When delivered after myocardial infarction, ESA augmented endogenous angiogenesis that translated to borderzone preservation and cardiac functional improvements in small and large animal models (Hiesinger et al. Circulation 2009; MacArthur et al. Circ Research 2014). Because a major limitation of endogenous repair is signal transience, we are currently exploring the utility of sustained release ESA by incorporating both simple and advanced hydrogel platforms in small and large animals (MacArthur et al. Circulation 2013).
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 (Cohen et al. Circulation Heart Failure 2014). Currently, this project is progressing through a pre-clinical large animal phase.
Principle among the concerns surrounding exogenous cell therapy is cell dispersion and survival. Embedding cells into protective tissue engineered constructs may address these limitations. We have started studying a unique cell culture technology that produces intact sheets of cells with naturally-produced extracellular matrix and intact cell-cell interactions. These sheets have excellent handling characteristics and can be implanted onto the heart; they function as a means of delivering cells while minimizing dispersion, promoting natural cellular interactions, and enhancing cell survival. To better mimic the architecture of a mature blood vessel, we have created EPC-smooth muscle cell (SMC) bi-level cell sheets to enhance survival of transplanted cells, to effect angiogenesis post-infarction, and to study the fate of transplanted EPCs (Shudo et al. Circulation 2013). We are currently working on creating EPC-SMC bi-level cell sheets from a more translatable source (bone marrow rather than aorta) to better realize the capacity of cell sheet technology for vasculogenesis with cellular therapeutics.
This represents one of the lab’s newer and more creative strategies for addressing the problem of tissue ischemia. Essentially, this approach targets the core problem of ischemia, which is the decoupling of oxygen and glucose delivery to carbon dioxide clearance. To restore balance to this equation, we have successfully employed a photosynthetic strategy where blue-green algae are introduced to ischemia tissue in the presence of light. These photosynthetic organisms capture the carbon dioxide and water from ischemic cells and recycle them to oxygen and glucose where light is the fuel to this reaction. We have demonstrated this in a rat model of acute myocardial ischemia. This work was recently presented at the American Association of Thoracic Surgeons annual meeting and won the C. Walton Lillehei Research Award. The manuscript is currently being prepared for submission.
Dr. Woo emphasizes the importance of research in advancing the field of cardiovascular surgery. He has served as the local principal investigator for multi-center clinical trials that test the newest cardiac surgical devices, ranging from sutureless valve prostheses to mechanical circulatory support devices (heart pumps). Additionally, therapies conceived in the laboratory are ultimately investigated for safety and efficacy in humans. Dr. Woo has been at the frontier of cell therapy for the surgical treatment for heart failure. He has tested direct EPC injection during coronary bypass surgery, and served as the lead principal investigator of the Cardiothoracic Surgical Trials Network’s (CTSN) investigation of the safety and efficacy of intramyocardial injection of mesenchymal precursor cells on myocardial function in LVAD recipients (Ascheim et al. Circulation 2014). Given the initial success, Dr. Woo and the CTSN have received additional funding to begin a phase II trial of mesenchymal precursor cells for the treatment of heart failure.
The Woo lab and Stanford Translational Animal Research Center is adept at testing cardiovascular therapies in small and large animal models. With access to a state-of-the-art hybrid operating theater, endovascular and minimally invasive surgical techniques have allowed us to be extremely successful in obtaining near 100% survival rates in our ovine model of ischemic cardiomyopathy. We frequently collaborate with other laboratories to help translate potential promising therapies.
Therapies that are effective in small animal models often fail to demonstrate utility in humans. Furthermore, animal models do not exist for a number of idiopathic diseases that affect the heart. Thus, our lab, in collaboration with Euan Ashley’s lab, is building a large biorepository of human cardiovascular tissue (both diseased and healthy). The biorepository exists to help investigators obtain the tissue necessary for gaining mechanistic insight into human cardiovascular diseases as well as test potential therapies. If interested in obtaining human tissue for cardiovascular research, please see the Contact Us page.