Development of 3D multi-cellular cardiac tissues for modeling delayed radiation-induced injury

The National Institutes of Health Office of the Director awarded The Leland Stanford Junior University a cooperative agreement totaling $1,077,676 on April 10, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to develop three-dimensional multi-cellular cardiac tissues for modeling delayed radiation-induced cardiac injury.

The recipient will establish a 3D cardiac-immune co-culture system using induced pluripotent stem cell (iPSC)-derived cardiomyocytes, endothelial cells, fibroblasts, and macrophages to simulate an immune-competent 3D microenvironment and validate optimized culture conditions in engineered cardiac tissues for physiological and inflammatory responses. Stanford will perform multi-omics analyses on irradiated engineered cardiac tissues and parallel animal models to identify molecular signatures of radiation-induced delayed cardiac remodeling via functional assessments of tissue contractility. The work will employ artificial intelligence and machine learning to integrate generated datasets, predict candidate medical countermeasures, and validate them in vitro and in vivo using a protracted irradiation mouse model. The recipient will conduct comprehensive evaluations to assess the efficacy of lead medical countermeasures in mitigating radiation-induced delayed cardiac remodeling.

Period of performance runs from April 10, 2026, through March 31, 2031. Work is performed in Palo Alto, California.

Abstract

Accidental exposure to ionizing radiation (IR) poses a significant risk for cardiovascular morbidity, a leading cause of mortality among irradiated populations. However, the mechanisms driving long-term cardiovascular risks remain poorly understood. IR disrupts immune homeostasis, exacerbating chronic inflammation and accelerating pathological remodeling. The current multi-PI U01 proposal seeks to address this knowledge GAP by developing an innovative extracorporeal system composed of human stem cell derivatives to identify biomarkers and medical countermeasures (MCMS) for radiation-induced delayed cardiac remodeling (RIDCR). In milestone 1, we will establish a 3D cardiac-immune CO-culture system using ipsc-derived cardiomyocytes, endothelial cells, fibroblasts, and macrophages to simulate the immune-competent 3D microenvironment. Optimized culture conditions will be validated in 3D engineered cardiac tissues (EHTS) for physiological and inflammatory responses. In milestone 2, we will perform multi-omics analyses on irradiated EHTS and parallel animal models to identify molecular signatures of RIDCR via multi-omics and functional assessments of tissue contractility. In milestone 3, AI/ML will integrate the generated datasets to predict candidate MCMS, which will be validated in vitro and tested in vivo using a protracted irradiation mouse model. Comprehensive evaluations will assess the efficacy of the lead MCM in mitigating RIDCR.