A Nodal to TGFβ Cascade Exerts Biphasic Control Over Cardiopoiesis

Rationale:The transforming growth factor-β (TGFβ) family member Nodal promotes cardiogenesis, but the mechanism is unclear despite the relevance of TGFβ family proteins for myocardial remodeling and regeneration. Objective:To determine the function(s) of TGFβ 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 TGFβ2. Both Nodal and TGFβ 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 TGFβ persists. At later stages (days 4–6), TGFβ suppresses the formation of cardiomyocytes from multipotent Kdr+ progenitors while promoting the differentiation of vascular smooth muscle and end...