UC San Diego

Advancements in cardiac regenerative therapies require understanding the early developmental decisions involved in cardiomyocyte (CM) specification and differentiation. While traditional CM differentiation approaches employ monolayer/2D protocols, they are unable to capture the complexity observed in vivo. This limitation has prompted the development of organoid/3D protocols, which is capable of recapitulating functional, structural, and metabolic features, as well as CM subtypes seen in vivo. Here, we aimed to characterize and genomically interrogate cardiac developmental models to elucidate and validate the mechanisms governing early CM and ventricular CM (vCM) development in order to direct key cardiac cell sources for cardiac therapies. Firstly, drawing upon scientific literature, we illustrated how developing cellularly complex cardiac models with the proper stimuli can be used for heart modeling and disease treatment. Secondly, we integrated multi-modal single-cell genomics studies with functional genetic screening to systematically discover and validate the coordinated gene regulatory networks and transcriptional regulators controlling the development of distinct human CM populations. Lastly, we extended these multi-modal genomic techniques to unravel the mechanisms underlying the specification and differentiation of vCMs for cell therapy-based heart failure treatment. Overall, these studies significantly enhance our understanding of early cardiac development, driving advancements in the field and paving the way for therapeutic intervention.