Year 3

Cardiovascular diseases remain the leading cause of death and disability in the United States. On average, an American suffers a coronary event every 34 seconds with one American dying of such an event every 1 minute and 23 seconds. Once the infarction has occurred, and even with optimal intervention, patients are prone to development of ischemic heart disease (IHD). Current therapies for IHD are incapable of rescuing necrotic tissue and recovering normal cardiac function. The only current curative therapy is heart transplantation; however donor organ supply is severely limited and the vast majority of patients die from congestive heart failure while on the transplant waiting list.

Cellular therapies are being explored as novel potential cure for IHD. Numerous cell therapies are currently under investigation for myocardial repair; however success rates remain modest. Typically, cells are injected in suspension into either the systemic or coronary vasculature or directly into the ischemic myocardium. Outcomes have clearly demonstrated the safety of these cell based therapies but clinical improvements have been modest. Major limitations that have been identified include inconsistent cell delivery methods and poor long term donor cells survival and retention. Reliable methods for delivery of therapeutic cells are therefore critically needed in order to improve cell based cardiac regenerative therapies.

Bioscaffolds have the potential to improve cell retention and localization to the site of injury. Porcine small intestinal submucosa extracellular matrix (SIS-ECM) is one such bioscaffold that may serve as a binding scaffold for MSCs. SIS-ECM itself has been found to exert a variety of beneficial pro-regenerative functions, hereunder modulation of the host chemotactic and immune response and release of large amounts of pro-angiogenic factors. Critically, SIS-ECM is already FDA approved for cardiac tissue repair after open heart surgery. MSCs are an ideal candidate for stem cell transplantation because of their ability to modulate the local tissue environment, induce local angiogenesis and recruit recipient effector populations. They also exhibit numerous pro-regenerative functions including immunomodulation by secreting a range of immunomodulatory factors and they are thus an ideal candidate for allogeneic transplantation. Furthermore, MSCs play a role in angiogenesis by secretion of angiogenic factors as well as chemotactic factors that facilitate recruitment of host stem and progenitor cells.

The overall goal of this project then has been to generate an MSC seeded SIS-ECM device for the treatment of IHD. The hypothesis is that the combination of MSCs and SIS-ECM will result in a device with regenerative properties that exceed either component alone. We have in the course of the project developed a porcine model that mimics the hallmarks of the human IHD by injecting an embolizing agent into the coronary artery. We have tested the proposed device in this model and monitored functional improvement as compared to control animals and animals receiving cells or ECM alone. We have also verified that human and porcine MSCs are phenotypically and functionally equivalent and finally, we have explored the possible mechanisms underlying such a therapeutic benefit both in the lab and in a rat myocardial infarct model.

With this final report, we consider this project to have been successfully executed and to have yielded significant new insight – not only into the utility of MSCs and SIS-ECM in the treatment of ischemic heart disease, but also in multiple areas of basic stem cell biology, animal modeling and translational research; all of which points far beyond the immediate scope of this project. We have completed the entire planned animal work and optimized all assays required for final analysis of the collected tissue and data. From the echocardiographic data, we expect to gain substantial insight into the effect of the different treatment options on the function of the ailing heart. We have also established new collaborations with colleagues who through sharing of tissue and data will enable us to analyze the hearts in far greater detail than first anticipated, thus substantially furthering our understanding of tissue regeneration. The data that will ultimately be derived from this huge body of work is, however, not at a stage of completion where we can offer any final conclusions regarding the main specific aims of the study. What can, however, be said with absolute certainty at this point is, that this project has contributed significant new insight into the area of regenerative medicine, large animal and translational research and beyond which could not have been achieved without the support of CIRM. Equally important, this work has laid the foundation for numerous future studies by both our team and by our colleagues at large that are certain to benefit heart disease patient in California and beyond.