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

Abstract

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 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 TGFβ, and 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.

BAF60 A, B, and Cs of muscle determination and renewal

“…However, other upstream regulators of signaling that program SWI/SNF selectivity are currently unknown; thus, a major task ahead is to link external cues to the control of chromatin remodeling. Potential pathways are suggested by functional interactions of BAF60c with Notch (Takeuchi et al 2007), Wnt/b-catenin (Klaus et al 2012) pathways in cardiac cells, and Nodal/TGFb signaling in ESC-derived cardiac progenitors (Cai et al 2012;M Mercola, unpubl. ), all of which might be consistent with the presence of multiple phosphorylation sites in BAF60c detected by mass spectrometry studies (PL Puri, unpubl.…”

Stem cell therapy for heart failure: Ensuring regenerative proficiency

“…Cues germane to the ventral endoderm of a developing embryo guide the anterolateral mesoderm ensuring definitive cardiac program engagement, and avoidance of alternative fates or uncontrolled growth [48]. Narrow windows defining developmental stages dictate the delicate nature in which cardiogenic cues need to be introduced to promote cardiogenesis from an embryonic stem cell source, exemplified in the complex dynamics of TGF-β superfamily signaling guiding pluripotent stem cell fate choices [49,50]. A systems biology-resolved cardiopoietic atlas revealed an integrated and tractable molecular network fundamental to lineage specification [51].…”

Mechanical Forces Reshape Differentiation Cues That Guide Cardiomyogenesis

“…Early during cardiac specification, Nodal activates TGFβ2 and the 2 signals act in concert to promote formation of cardiac mesoderm. 103 Although Nodal undergoes autoinhibition after its early expression, TGFβ2 expression persists and continues on to mediate cardiomyogenesis. Inhibition of TGFβ2 with RNA interference enhances expression of cardiac marker Myh2 , demonstrating its role in blocking cardiomyocyte differentiation, whereas treatment with recombinant TGFβ2 upregulates expression of Pecam1 and Myh11 , markers of endothelial and smooth muscle cells.…”