Quentin Jallerat — 2011-12 Fellow
Cardiovascular disease is the leading cause of death in developed countries, accounting for 34.3% of deaths in the US. Myocardial infarction (MI), caused by ischemia in the heart, is among the most common cardiovascular diseases. Unfortunately, the only viable treatment is heart transplant, and only 10% of heart failure patients ever get a donor heart. Progress in tissue engineering and regenerative medicine has enabled the development of treatments for many diseases and injuries in other organs. However, the heart still presents two major challenges to current researchers: (i) overcoming the incapacity of adult cardiomyocytes to proliferate and replace damaged cells and (ii) reproducing the density of capillaries supplying nutrients to the tissue. While there are about 600 capillaries per mm2 of skeletal muscle, the myocardium vasculature is 4 times denser with about 2,400 capillaries per mm2 for an intercapillary distance of 20 um.
Stem cells are the answer to overcoming the incapacity of adult cardiomyocytes to proliferate and regenerate heart muscle. Cardiomyocytes can now be derived from a variety of cell sources including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), adult stem cells, and transdifferentiated from fibroblasts. Current therapies include injecting cells at the site of injury, or grafting a polymeric scaffold previously seeded with cells. However, despite being able to derive these cells, organizing them into a cardiac tissue and integration in the native tissue is limited.
Currently, there is no solution to regenerating cardiac muscle in 3-D with a microvascular system. State-of-the-art relies on growing isotropic cardiac cells sheet on thermosensitive poly(N-isopropylacrylamide) (PIPAAm) surfaces. Grafting of four-layer sheets in infarcted rats has shown promising results by increasing the ventricular wall thickness and improving cardiac function, but capillaries from the host must slowly grow into the graft, limiting graft thickness to <100 um. Better control can be achieved by mimicking the extracellular matrix (ECM) which contains structural and chemical cues that control tissue organization neovascularization. For example, decellularized hearts and lungs from rat were treated to remove the cells while preserving the ECM. After being seeded with stem cells, the cells differentiated and proliferated according to the original tissue structure, with hearts being able to beat and lungs being able to breathe, showing the importance of the ECM in the formation of the vasculature. However, decellularized organs have limitations in availability, ECM quality and rate of vascularization and anastomoses to the host blood supply.
We propose an improved method to engineer 3-D cardiac muscle and control vascularization. To do this we will use a biomimetic approach to rebuild the ECM from the bottom up the same way cells do in tissues. By templating specific ECM proteins, we will grow cardiac cell sheets and control the development of the capillary network. The proposed study will establish these novel tissue engineering techniques in vitro, with the ultimate goal of clinical translation for improving integration and vascularization of cardiac cell sheet grafting in vivo.