A Nodal to TGFβ Cascade Exerts Biphasic Control Over Cardiopoiesis
Rationale: The Transforming Growth Factorβ (TGFβ) family member Nodal promotes cardiogenesis, but the mechanism is unclear despite the relevance of TGFβ family proteins for myocardial remodeling and regeneration.
Objective: Determine the function(s) of TGFβ family members during stem cell cardiogenesis.
Methods and Results: Murine embryonic stem cells (mESCs) 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 ESC cultures at day 0-2 of differentiation. However, Nodal expression declines by day 4 due to feedback inhibition whereas TGFβ persists. At later stages (day 4-6), TGFβ suppresses the formation of cardiomyocytes from multipotent Kdr+ progenitors, while promoting the differentiation of vascular smooth muscle and endothelial cells.
Conclusions: Nodal induces TGFβand both stimulate the formation of multipotent cardiovascular Kdr+ progenitors. TGFβ; however, becomes uniquely responsible for controlling subsequent lineage segregation by stimulating vascular smooth muscle and endothelial lineages and simultaneously blocking cardiomyocyte differentiation.
- Received March 28, 2012.
- Accepted July 11, 2012.
- Copyright © 2012, American Heart Association