A Nodal-to-TGFβ Cascade Exerts Biphasic Control Over Cardiopoiesis

Rationale: The transforming growth factor-beta (TGF beta) family member Nodal promotes cardiogenesis, but the mechanism is unclear despite the relevance of TGF beta family proteins for myocardial remodeling and regeneration. Objective: To determine the function(s) of TGF beta family members during stem cell cardiogenesis. Methods and Results: Murine embryonic stem cells were engineered with a constitutively active human type I Nodal receptor (caACVR1b) to mimic activation by Nodal and found to secrete a paracrine signal that promotes cardiogenesis. Transcriptome and gain- and loss-of-function studies identified the factor as TGF beta 2. Both Nodal and TGF beta induced early cardiogenic progenitors in embryonic stem cell cultures at day 0 to 2 of differentiation. However, Nodal expression declines by day 4 due to feedback inhibition, whereas TGF beta persists. At later stages (days 4-6), TGF beta suppresses the formation of cardiomyocytes from multipotent Kdr(+) progenitors while promoting the differentiation of vascular smooth muscle and endothelial cells. Conclusions: Nodal induces TGF beta, and both stimulate the formation of multipotent cardiovascular Kdr(+) progenitors. TGF beta, however, becomes uniquely responsible for controlling subsequent lineage segregation by stimulating vascular smooth muscle and endothelial lineages and simultaneously blocking cardiomyocyte differentiation. (Circ Res. 2012;111:876-881.)