Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells

Abstract

Summary 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.

Apoptosis Evaluation in Circulating CD34+-Enriched Hematopoietic Stem and Progenitor Cells in Patients with Abnormally Increased Production of Endogenous Glucocorticoids in Course of Cushing’s Syndrome

“…We reported here for the first time that CD34+-enriched HSPCs from patients with CS expressed GR alpha at protein levels ( Figure 1 ). It has been documented that expression of GR was present in peripheral blood lineage-committed hematopoietic cell subsets, including lymphoid and myeloid cell lineages [ 26 , 27 ], or other stem cell types, such as mesenchymal stem cells (MSC) [ 28 ], neural stem cells (NSC) [ 29 ] or even embryonic stem cells (ESC) [ 30 ] and periodontal ligament stem cells (PLSC) [ 31 ]. Notably, only a few studies have investigated expression of GR in hematopoietic stem cells of different origin, including embryonic [ 32 ] or cord blood-derived [ 33 ].…”

Mutations in the zebrafish hmgcs1 gene reveal a novel function for isoprenoids during red blood cell development

“…However, the function of the CSP might not be limited to cell death or stress mechanisms because previously published work has indicated a regulatory function for cholesterol and its derivatives at the level of cellular differentiation. [56][57][58][59][60][61][62][63] Future analyzes at unique stages of differentiation in different model systems is likely to identify the exact cellular mechanisms underlying the phenotypic alteration we describe. The closely related zebrafish mutant of hmgcrb will be of great utility because we hypothesize that mutation of hmgcrb 37 will produce overlapping phenotypes with the Vu57 allele.…”

Comprehensive proteogenomic analysis of human embryonic and induced pluripotent stem cells

“…Moreover, there are evidences suggesting a co‐existence of both oxidative and glycolytic metabolisms in stem cells . Cholesterol contributes to the maintenance of self‐renewal in ESCs by regulation of LIF‐induced signalling, and its derivatives, such as glucocorticoids, regulate cell fate during early development and seem to control cardiac differentiation in mESCs . Panopoulus et al demonstrated that the level of some unsaturated fatty acids such as arachidonic acid, implicated in the cholesterol homeostasis regulation, differs quantitatively between iPSCs and ESCs .…”

“…38 Cholesterol contributes to the maintenance of self-renewal in ESCs by regulation of LIF-induced signalling, and its derivatives, such as glucocorticoids, regulate cell fate during early development and seem to control cardiac differentiation in mESCs. 39 Panopoulus et al 40 demonstrated that the level of some unsaturated fatty acids such as arachidonic acid, implicated in the cholesterol homeostasis regulation, differs quantitatively between iPSCs and ESCs. 41 Another pathway that resulted enriched in hiPSC-1 vs hESCs is represented by the anti-oxidant system as shown by the over-expression in hiPSC-1 of the glucose transporter SLC2A3, previously associated with an anti-oxidant role.…”