Examining the risk of chronic opioid use on cardiac development in mice and human stem cell derived vascularized cardiac organoids.

About This Grant

PROJECT SUMMARY/ABSTRACT Up to 22% of pregnant women either receive opioid pain medications or misuse opioids, consequently exposing their fetuses to potential adverse outcomes such as congenital heart defects, stillbirths and disrupted early cardiovascular development (eCVD). While cessation of opioid use might not be possible, effective and individualized pain management during pregnancy is critical and strongly warranted. However, the precise details of how opioid timing, dose, and type affecting eCVD remain poorly understood. There is an urgent need to investigate the impact of opioids on eCVD in models that faithfully simulate human embryonic development. Without such knowledge, establishing a guide for opioid treatment during pregnancy to mitigate adverse cardiovascular outcomes in neonates, remains unlikely. We have developed a novel cell platform using human pluripotent stem cell (hPSC)-derived vascularized organoids (vCOs) to elucidate the effects of drugs on eCVD. The combination of a genetically modified embryonic stem cell (ESC) reporter line expressing cardiomyocyte (CM), endothelial cell (EC), and smooth muscle cell specific fluorescence proteins in combination with our newly established differentiation protocol, allows us to evaluate the impact of opioids on CM and EC development and their role in eCVD. Genetic profiling confirms that our platform mimics normal eCVD during the first six weeks of human embryogenesis. The platform's high throughput nature and applicability in human induced pluripotent stem cells positions it as a promising translational tool to predict the cell-type-specific effects of various opioids on structure, function, vascular network formation during patient specific eCVD. We now seek to acquire robust experimental evidence demonstrating our platform's efficacy in modelling the impact of maternal opioid use on offspring eCVD. Our central hypothesis posits that antenatal opioid exposure disrupts both structural and functional eCVD, and that hPSC-derived vCOs provide a personalize and robust platform for predicting these detrimental effects. Our proposal seeks to accomplish the following key objectives: (1) to validate our newly developed cell platform and its predictive capabilities, (2) to assess the impact of opioids on eCVD and survival in vivo using a mouse model, and (3) to develop a personalized risk profile for opioid-induced eCVD defects using hPSC-derived vCOs. This hypothesis is supported by preliminary data indicating an increased number of miscarriages in opioid-treated pregnant mice, along with cardiac malformations in their offspring. In addition, we observed opioid-dependent transcriptomic alterations and disturbed CM and EC interactions in vCOs. The proposed research aims to provide a comprehensive understanding of the mechanisms underlying opioid- associated congenital cardiovascular defects, and to explore strategies to prevent their occurrence. This knowledge will form the groundwork for developing evidence-based, personalized therapeutic interventions for future clinical applications.