Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells
Year: 2015
Type: article
Abstract: Aside from its role in cell membrane integrity, cholesterol is a key component in steroid hormone production. The vital functions of steroid hormones such as estrogen, testosterone, glucocorticoids (Gcrts) and mineralocorticoids (Mnrts) in perinatal and adult life are well understood; however, their role during early embryonic development remains largely unexplored. Here we show that siRNA-mediated perturbation of steroid hormone production during mesoderm formation has important consequences on cardiac differentiation in mouse embryonic stem cells (mESC). Both Gcrts and Mnrts are capable of driving cardiac differentiation in mESC. Interestingly, the Gcrt receptor is widely expressed during gastrulation in the mouse, and is exclusively localized in the nuclei-and thus active-in visceral endoderm cells, suggesting that it functions much earlier than previously anticipated. We therefore studied Gcrt signaling in mESC as a model of the gastrulating embryo, and found that Gcrt signaling regulates expression of the transcription factor Hnf4a and the secreted Nodal and BMP inhibitor Cer1 in the early visceral endoderm. RNAi-mediated knockdown of Gcrt function blocked cardiomyocyte differentiation, with limited effects on other cardiovascular cell types including vascular endothelial cells and smooth muscle. Furthermore, the cardiogenic effect of Gcrts required Hnf4a and paracrine Cer1. These results establish a novel function for cholesterol-derived steroid hormones and identify Gcrt signaling in visceral endoderm cells as a regulator of Cer1 and cardiac fate.
Source: Stem Cell Research
Authors: Joaquim Cabral-Teixeira, Almudena Martinez-Fernandez, Wenqing Cai, Andre Terzic, Mark Mercola, Erik Willems
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,360
Funders: California Institute for Regenerative Medicine, American Heart Association, Fondation Leducq, Ministry of Natural Resources and Tourism, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: microRNAs and Integrative Control on Cardiopoiesis , G410557130, San Diego Skeletal Muscle Research Center, G5462587459, Type III CIRM Stem Cell Research Training Program, Myocardial Angiogenesis and Cardioprotection, Molecular Biology of Heart Induction, G9000023887, G9000102658, Cancer Center Support Grant (CCSG)
OpenAlex ID: W273006015