A Case for Revisiting Nodal Signaling in Human Pluripotent Stem Cells

Abstract

Nodal is a transforming growth factor-β (TGF-β) superfamily member that plays a number of critical roles in mammalian embryonic development. Nodal is essential for the support of the peri-implantation epiblast in the mouse embryo and subsequently acts to specify mesendodermal fate at the time of gastrulation and, later, left-right asymmetry. Maintenance of human pluripotent stem cells (hPSCs) in vitro is dependent on Nodal signaling. Because it has proven difficult to prepare a biologically active form of recombinant Nodal protein, Activin or TGFB1 are widely used as surrogates for NODAL in hPSC culture. Nonetheless, the expression of the components of an endogenous Nodal signaling pathway in hPSC provides a potential autocrine pathway for the regulation of self-renewal in this system. Here we review recent studies that have clarified the role of Nodal signaling in pluripotent stem cell populations, highlighted spatial restrictions on Nodal signaling, and shown that Nodal functions in vivo as a heterodimer with GDF3, another TGF-β superfamily member expressed by hPSC. We discuss the role of this pathway in the maintenance of the epiblast and hPSC in light of these new advances.

Resveratrol alleviates enterotoxigenicEscherichia coliK88-induced damage by regulating SIRT-1 signaling in intestinal porcine epithelial cells

“…53,54 To better understand the cell viability improvement by resveratrol during ETEC K88 infection, we also detected the gene expression of TGFB1 and KLF4, two important markers for cell growth and differentiation. 55,56 Consistent with the reduction of cell viability, ETEC K88 treatment decreased the gene expression of TGFB1 and KLF4, which was reversed by resveratrol pretreatment, indicating that IPEC-1 cells supplied with resveratrol gained a greater ability to deal with ETEC K88 infection. Moreover, our research suggested that resveratrol protected tight junctions at mRNA and protein levels in ETEC K88treated cells.…”

Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing

“…6f, g ). Similarly, the expression of BMP4, NODAL and CRIPTO (a NODAL co-receptor 35 , 48 ) was unchanged in GPC4sh (Supplementary Fig. 6f, g ).…”

“…To trigger hiPSC differentiation along these lineages we exposed cells to BMP4 and ACTIVIN A (Fig. 2c), a commonly used surrogate to activate aspects of the NODAL signaling pathway in vitro [33][34][35][36][37] . We then evaluated the differentiation profile of control and GPC4sh hiPSCs by using RT-qPCR analysis following lineage-specific markers.…”

DNA methylation supports accelerated biological age in Type 2 Diabetes which can be reversed with pharmacological treatments: Retrospective Cohort Study

“…Pathway enrichment in whole blood showed pathways involved in biogenesis of mitochondria, and fibronectin matrix formation. NODAL signaling was also upregulated in whole blood and is involved in maintaining the human pluripotent stem cell population 19 . Upregulation of pathways involved in inflammation were also shown, such as the AIM2 inflammasome 20 , which is involved in inflammatory signaling and inflammatory related apoptosis.…”

“…18 Pathway enrichment in whole blood showed pathways involved in biogenesis of mitochondria, and fibronectin matrix formation. NODAL signaling was also upregulated in whole blood and is involved in maintaining the human pluripotent stem cell population 19 .…”