A case for revisiting Nodal signaling in human pluripotent stem cells

Nodal is a transforming growth factor-beta (TGF-beta) 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 that Nodal functions in vivo as a heterodimer with GDF3, another TGF-beta 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.

Automated summary

Nodal is a crucial factor in mammalian embryonic development and the maintenance of pluripotent stem cells. Its signaling pathway may play an important role in regulating self-renewal in hPSC.