Generation of four-chambered hearts through organoid fusions

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Project Summary Congenital heart defects (CHDs) account for 1-2% of all live births in the U.S. More than 90% of these diseases are attributed to defects in heart valves and septum; Of which, few have been modeled in mice likely due to species differences and genetic complexities behind the disease. As an alternative approach, human induced pluripotent stem cells (hiPSC), which has demonstrated great success in mimicking other diseases, falls short in the modeling of CHDs, especially in regard to spatial sensitive mechanisms like those involved in heart chamber development. However, with the emergence of organoids, the field is making significant strides toward better CHD models. Currently, the limitations of using organoids resides in the structures integrity when compared to the endogenous tissue, yet, the potential for CHD modelling is unmatched. Here I propose using a novel method based on the organoid fusion principle to generate hearts with anatomically features: chambers, valves and septum. To do this, we will first fuse one atrial and one ventricular organoid to create the cardiac valves. Next, we will further extend this process to advance the formation of the valves and begin formation of the septum by fusing two atrial and two ventricular organoids. Furthermore, we plan to use several of our hiPSC lines either carrying CHD mutations or being directly reprogrammed from patients diagnosed with CHDs to generate fused organoids that will allow us to model the disease progressions in patients. We anticipate that the successful application of these techniques will offer significant improvements in modeling the normal human heart development and congenital heart defects, with the ultimate goal of preventing and treating congenital heart diseases.