Defects in heart formation during embryonic and fetal development likely contribute to miscarriages, which terminate up to 25% of all pregnancies, and Congential Heart Defects (CHDs), which are among the most common birth defects. Environmental factors may influence miscarriages and up to 80% of all CHDs, but little is known about how such chemicals affect formation of the heart during early embryonic differentiation. The goal of this SBIR project is to develop a Cardiopoiesis Assay (heart formation assay) to enable testing of compounds to determine if they influence the emergence of cardiac myocytes from multipotent mesodermal progenitors, a critical, early decision point, in heart formation. During the previous Phase I portion of the project, a version of the assay was developed using mouse embryonic stem cells, and this assay has proven useful in identifying chemicals, siRNAs, and miRs that modify cardiac differentiation. For Phase II, we propose to develop the assay using human induced pluripotent stem cells (hiPSCs), which will be derived from multiple donors to increase the genetic diversity represented by the assay. The Cardiopoiesis Assay will be useful in predicting whether chemical compounds affect heart formation in the human embryo, which is of critical importance to human health. The assay will be of interest to government agencies in the US (such as the Environmental Protection Agency) and worldwide, concerned with environmental toxicology.
Defects of the heart are the most common birth defects and may be caused, in part, by toxic compounds from the environment that interfere with heart formation prior to birth. We propose to develop a test system to screen chemicals for dangerous effects on heart formation. We propose to use human stem cells, which we will derive from skin samples obtained from volunteer donors (the skin samples are obtained by a painless procedure that is risk-free). Such stem cells can be cultured in a manner that they form beating heart cells, in laboratory dishes. We will develop a procedure to test if chemicals prevent formation of heart cells from stem cells; as such chemicals are likely to cause heart birth defects.
| El Harane, Nadia; Kervadec, Anaïs; Bellamy, Valérie et al. (2018) Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors. Eur Heart J 39:1835-1847 |
| Yu, Michael S; Spiering, Sean; Colas, Alexandre R (2018) Generation of First Heart Field-like Cardiac Progenitors and Ventricular-like Cardiomyocytes from Human Pluripotent Stem Cells. J Vis Exp : |
| Cunningham, Thomas J; Yu, Michael S; McKeithan, Wesley L et al. (2017) Id genes are essential for early heart formation. Genes Dev 31:1325-1338 |
| McKeithan, Wesley L; Savchenko, Alex; Yu, Michael S et al. (2017) An Automated Platform for Assessment of Congenital and Drug-Induced Arrhythmia with hiPSC-Derived Cardiomyocytes. Front Physiol 8:766 |
