PhD Student Cedars-Sinai Medical Center Los Angeles, United States
Abstract: The heart is the first organ to form in the human body and is regulated by genetic, epigenetic, and molecular signaling dynamics. When these processes are disrupted, it can result in the formation of Congenital Heart Defects (CHD), which are the most common & severe birth defect affecting 1% of newborns each year. Notch signaling is a conserved signaling pathway crucial for cell fate decisions during mammalian development, although the exact mechanism it plays in cardiogenesis is not fully understood. Dysfunction in Notch signaling has been linked to congenital defects such as Hypoplastic Left Heart Syndrome. By understanding the molecular mechanisms driving cardiogenesis, we can apply these finding to advancing regenerative medicine applications and developing therapies for congenital heart defects. Previous induced pluripotent stem cell (iPSC) modeling approaches for studying cardiac development have employed 2D cell culture, but full understanding of the molecular mechanisms involves spatial and molecular profiling of multiple cell types which are involved in coordinating the development of the heart. Recent advances using organoid modeling has further advanced our ability to understand the cellular and morphological events which occur during heart development. Here, we utilize pharmacological inhibition of Notch signaling in a human iPSC derived cardiac organoid developmental model to further evaluate the role notch signaling plays in cardiogenesis. Cardiac organoids were treated with Notch inhibitor DAPT throughout the course of a 12-day cardiac differentiation. Organoids were imaged & collected throughout various developmental stages. DAPT treated cardiac organoids exhibited decreased size, impaired chamber formation and reduced contractility. Whole organoid immunofluorescence showed changes in cardiac progenitor and cardiomyocyte populations compared to DMSO control. Overall, these findings further highlight the advantage of cardiac organoid modeling for studying cardiogenesis and will allow us to gain a greater understanding of the complex interactions of Notch signaling and better understand its role in proper cardiac development.
Funding Source: This work was supported by California Institute for Regenerative Medicine (CIRM EDUC4-12751)
